Bicyclic heterocyclyl derivatives as irak4 inhibitors

ABSTRACT

wherein A, Y, Z, X1, X2, X3, R1, R3, ‘m’, ‘n’ and ‘p’ have the meanings given in the specification and pharmaceutically acceptable salt or stereoisomer thereof that are useful in the treatment and prevention of diseases or disorder, in particular their use in diseases or disorder mediated by kinase enzyme, particularly IRAK4 enzyme. The present invention also provides pharmaceutical composition comprising at least one of the compounds of compound of formula (I) together with a pharmaceutically acceptable carrier, diluent or excipient therefor.

This application is a continuation of U.S. Ser. No. 15/667,173, filedAug. 2, 2017, now U.S. Ser. No. 10/047,104, issued on Aug. 14, 2018,which is a continuation of U.S. Ser. No. 15/111,000, filed on Jul. 12,2016, now U.S. Pat. No. 9,732,095, issued on Aug. 15, 2017, which is theU.S. national phase of International Patent Application No.PCT/IB2015/050217, filed Jan. 12, 2015, which claims the benefit ofIndian provisional applications 158/CHE/2014 filed on Jan. 13, 2014 and3000/CHE/2014 filed on Jun. 20, 2014, the contents of which are herebyincorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to compounds useful for treatment of cancer andinflammatory diseases associated with interleukin-1 receptor associatedkinase (IRAK) and more particularly compounds that modulate the functionof IRAK-4. The invention also provides pharmaceutically acceptablecompositions comprising compounds of the present invention and methodsof using said compositions in the treatment of diseases associated withIRAK-4

BACKGROUND OF THE INVENTION

Interleukin-1 (IL-1) Receptor-Associated Kinase-4 (IRAK-4) is aserine/threonine kinase enzyme that plays an essential role in signaltransduction by Toll/IL-1 receptors (TIRs). Diverse IRAK enzymes are keycomponents in the signal transduction pathways mediated by interleukin-1receptor (IL-1R) and Toll-like receptors (TLRs) (Janssens, S, et al.Mol. Cell. 11, 2003, 293-302). There are four members in the mammalianIRAK family: IRAK-1, IRAK-2, IRAK-M and IRAK-4. These proteins arecharacterized by a typical N-terminal death domain that mediatesinteraction with MyD88-family adaptor proteins and a centrally locatedkinase domain. The IRAK proteins, as well as MyD88, have been shown toplay a role in transducing signals other than those originating fromIL-1R receptors, including signals triggered by activation of IL-18receptors (Kanakaraj, et al. J. Exp. Med. 189(7):1999, 1129-38) and LPSreceptors (Yang, et al., J. Immunol. 163, 1999, 639-643). Out of fourmembers in the mammalian IRAK family, IRAK-4 is considered to be the“master IRAK”. Under overexpression conditions, all IRAKs can mediatethe activation of nuclear factor-kB (NF-kB) and stress-induced mitogenactivated protein kinase (MAPK)-signaling cascades. However, only IRAK-1and IRAK-4 have been shown to have active kinase activity. While IRAK-1kinase activity could be dispensable for its function in IL-1-inducedNF-kB activation (Kanakaraj et al, J. Exp. Med. 187(12), 1998,2073-2079) and (Xiaoxia Li, et al. Mol. Cell. Biol. 19(7), 1999,4643-4652), IRAK-4 requires its kinase activity for signal transduction(Li S, et al. Proc. Natl. Acad. Sci. USA 99(8), 2002, 5567-5572) and(Lye, E et al, J. Biol. Chem. 279(39); 2004, 40653-8). Given the centralrole of IRAK4 in Toll-like/IL-1R signalling and immunologicalprotection, IRAK4 inhibitors have been implicated as valuabletherapeutics in inflammatory diseases, sepsis and autoimmune disorders(Wietek C, et al, Mol. Interv. 2: 2002, 212-215).

Mice lacking IRAK-4 are viable and show complete abrogation ofinflammatory cytokine production in response to IL-1, IL-18 or LPS(Suzuki et al. Nature, 416(6882), 2002, 750-756). Similarly, humanpatients lacking IRAK-4 are severely immunecompromised and are notresponsive to these cytokines (Medvedev et al. J. Exp. Med., 198(4),2003, 521-531 and Picard et al. Science 299(5615), 2003, 2076-2079).Knock-in mice containing inactive IRAK4 were completely resistant tolipopolysaccharide- and CpG-induced shock (Kim T W, et al. J Exp Med204: 2007, 1025-36) and (Kawagoe T, et al. J Exp Med 204(5): 2007,1013-1024) and illustrated that IRAK4 kinase activity is essential forcytokine production, activation of MAPKs and induction of NF-κBregulated genes in response to TLR ligands (Koziczak-Holbro M, et al. JBiol Chem; 282(18): 2007; 13552-13560). Inactivation of IRAK4 kinase(IRAK4 KI) in mice leads to resistance to EAE due to reduction ininfiltrating inflammatory cells into CNS and reduced antigen specificCD4+ T-cell mediated IL-17 production (Kirk A et al. The Journal ofImmunology, 183(1), 2009, 568-577).

The crystal structures revealed that IRAK-4 contains characteristicstructural features of both serine/threonine and tyrosine kinases, aswell as additional novel attributes, including the unique tyrosinegatekeeper residue. Structural analysis of IRAK-4 revealed theunderlying similarity with kinase family; ATP-binding cleft sandwichedbetween a bilobal arrangement. The N-terminal lobe consists of mainly ofa twisted five-stranded antiparallel beta-sheet and one alpha-helix andthe larger C-terminal lobe are predominantly alpha-helical. Yet, thestructure reveals a few unique features for IRAK-4 kinase, including anadditional alpha-helix from the N-terminal extension in the N-terminallobe, a longer loop between helices alpha-D and alpha-E and asignificantly moved helix alpha G as well as its adjoining loops. TheATP-binding site in IRAK-4 has no deep pocket in the back but has afeatured front pocket. This uniquely shaped binding pocket provides anexcellent opportunity for designing IRAK-4 inhibitors.

The development of IRAK-4 kinase inhibitors has generated several novelclasses of protein binders which includes thiazole and pyridine amides(George M Buckley, et al. Bioorg. Med. Chem. Lett., 18(11), 2008,3211-3214), aminobenzimidazoles (Powers J P, et al. Bioorg. Med. Chem.Lett., 16(11), 2006, 2842-2845), Imidazo[1,2-a] pyridines (Buckley G M,et al. Bioorg. Med. Chem. Lett. 18(11), 2008, 3656-3660) and (Buckley G,et al. Bioorg. Med. Chem. Lett. 18(11), 2008, 3291-3295),imidazo[1,2-b]pyridazines and benzimidazole-indazoles (WO2008030579;WO2008030584). Apparently, all of them are still in the earlypreclinical stage.

Despite various disclosures on different kinase inhibitors, however,with the rise in number of patients affected by kinase enzyme mediateddiseases, there appears to be unmet need for newer drugs that can treatsuch diseases more effectively. There is still need for newer kinaseinhibitors including multikinase inhibitors, which may be further usefulin treatment of disorders owing to variations in various kinasesactivity and possessing broader role. They may also be useful as part ofother therapeutic regimens for the treatment of disorders, alone or incombination with protein kinase compounds well known by the one skilledin the art.

OBJECTIVES OF THE INVENTION

One objective herein is to provide bicyclic heterocyclyl compounds offormula (I) or a pharmaceutically acceptable salt or a stereoisomerthereof, as kinase inhibitors, particularly IRAK4 inhibitors.

Another objective is to provide a pharmaceutical composition comprisingthe compound of formula (I) or a pharmaceutically acceptable salt or astereoisomer thereof and at least one pharmaceutically acceptableexcipient such as a pharmaceutically acceptable carrier or diluent.

Yet another objective is to provide a use of bicyclic heterocyclylderivatives of formula (I) or a pharmaceutically acceptable salt or astereoisomer thereof, for the treatment and prevention of diseases ordisorders, in particular their use in diseases or disorder where thereis an advantage in inhibiting kinase enzyme, more particularly IRAK4enzyme.

SUMMARY OF THE INVENTION

In one aspect according to the present invention, it comprises bicyclicheterocyclyl derivatives of formula (I)

or a pharmaceutically acceptable salt or a stereoisomer thereof;wherein,

X₁ and X₃ independently are CH or N; X₂ is CR₂ or N; provided one andnot more than one of X₁, X₂ or X₃ is N;

A is O or S;

Y is —CH₂— or O;

Ring Z is aryl or heterocyclyl;

R₁, at each occurrence, is independently halo or optionally substitutedheterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl,halo, hydroxyl, hydroxyalkyl or —NR_(a)R_(b);

R₂ is hydrogen, optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted heterocyclyl or —NR_(a)R_(b);wherein the substituent is alkyl, amino, halo or hydroxyl;

R₃, at each occurrence, is alkyl or hydroxyl;

R_(a) and R_(b) are independently hydrogen, alkyl, acyl or heterocyclyl;

‘m’ and ‘n’ are independently 0, 1 or 2;

‘p’ is 0 or 1.

In yet another aspect, the present invention provides a pharmaceuticalcomposition comprising the compound of formula (I) or a pharmaceuticallyacceptable salt or a stereoisomer thereof and at least onepharmaceutically acceptable excipient such as a pharmaceuticallyacceptable carrier or diluent.

In yet another aspect, the present invention relates to the preparationof the compounds of formula (I).

In yet further aspect of the present application, it provides use ofbicyclic heterocyclyl derivatives of formula (I) or a pharmaceuticallyacceptable salt or a stereoisomer thereof, for the treatment andprevention of diseases or disorder mediated by IRAK4 enzyme.

More particularly, the invention relates to the use of bicyclicheterocyclyl derivatives of formula (I) pharmaceutically acceptablesalts and stereoisomers thereof, including mixtures thereof in allratios, as a medicament, by inhibiting IRAK or IRAK4 or other relatedkinases.

Bicyclic heterocyclyl derivatives of formula (I) of the presentinvention possess therapeutic role of inhibiting IRAK or IRAK4 or otherrelated kinases useful in the area of diseases and/or disorders include,but are not limited to cancers, allergic diseases and/or disorders,autoimmune diseases and/or disorders, inflammatory diseases and/ordisorder and/or conditions associated with inflammation and pain,proliferative diseases, hematopoietic disorders, haematologicalmalignancies, bone disorders, fibrosis diseases and/or disorders,metabolic disorders, muscle diseases and/or disorders, respiratorydiseases and/or disorders, pulmonary diseases and/or disorders, geneticdevelopmental diseases and/or, neurological and neurodegenerativediseases and/or disorders, chronic inflammatory demyelinatingneuropathies, cardiovascular, vascular or heart diseases and/ordisorders, ophthalmic/ocular diseases and/or disorders, wound repair,infection and viral diseases. Therefore, inhibition of one or morekinases would have multiple therapeutic indications.

DETAILED DESCRIPTION OF THE INVENTION

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as is commonly understood by one of skill in artto which the subject matter herein belongs. As used in the specificationand the appended claims, unless specified to the contrary, the followingterms have the meaning indicated in order to facilitate theunderstanding of the present invention.

The singular forms “a”, “an” and “the” encompass plural referencesunless the context clearly indicates otherwise.

As used herein, the terms “optional” or “optionally” mean that thesubsequently described event or circumstance may occur or may not occurand that the description includes instances where the event orcircumstance occurs as well as instances in which it does not. Forexample, “optionally substituted alkyl” refers to that ‘alkyl’ may besubstituted as well as where the alkyl is not substituted.

It is understood that substituents and substitution patterns on thecompounds of the present invention can be selected by one of ordinaryskilled person in the art to result chemically stable compounds whichcan be readily synthesized by techniques known in the art, as well asthose methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.

As used herein, the term “optionally substituted” refers to thereplacement of one to six hydrogen radicals in a given structure withthe radical of a specified substituent including, but not limited to:halo, cyano, alkyl, haloalkyl, alkoxy, haloalkoxy, alkenyl, alkynyl,aryl, heterocyclyl, amino, cyano, nitro, alkylamino, arylamino,alkylaminoalkyl, arylaminoalkyl, hydroxyl, hydroxyalkyl, cycloalkyl,aryl, heterocyclic and aliphatic. It is understood that the substituentmay be further substituted.

As used herein, the term “alkyl” refers to saturated aliphatic groups,including but not limited C₁-C₁₀ straight-chain alkyl groups or C₁-C₁₀branched-chain alkyl groups. Preferably, the “alkyl” group refers toC₁-C₆ straight-chain alkyl groups or C₁-C₆ branched-chain alkyl groups.Most preferably, the “alkyl” group refers to C₁-C₄ straight-chain alkylgroups or C₁-C₄ branched-chain alkyl groups. Examples of“alkyl” include,but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, n-butyl,sec-butyl, tert-butyl, 1-pentyl, 2-pentyl, 3-pentyl, neo-pentyl,1-hexyl, 2-hexyl, 3-hexyl, 1-heptyl, 2-heptyl, 3-heptyl, 4-heptyl,1-octyl, 2-octyl, 3-octyl or 4-octyl and the like. The “alkyl” group maybe optionally substituted.

The term “acyl” refers to a group R—CO— wherein R is an alkyl groupdefined above. Examples of ‘acyl’ groups are, but not limited to,CH₃CO—, CH₃CH₂CO—, CH₃CH₂CH₂CO— or (CH₃)₂CHCO—.

As used herein, the term “alkoxy” refers to a straight or branched,saturated aliphatic C₁-C₁₀ hydrocarbon radical bonded to an oxygen atomthat is attached to a core structure. Preferably, alkoxy groups have oneto six carbon atoms. Examples of alkoxy groups include but are notlimited to methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy,tert-butoxy, pentoxy, 3-methyl butoxy and the like.

As used herein, the term “haloalkyl” refers to alkyl group (as definedabove) is substituted with one or more halogens. A monohaloalkylradical, for example, may have a chlorine, bromine, iodine or fluorineatom. Dihalo and polyhaloalkyl radicals may have two or more of the sameor different halogen atoms. Examples of haloalkyl include, but are notlimited to, chloromethyl, dichloromethyl, trichloromethyl,dichloroethyl, dichloropropyl, fluoromethyl, difluoromethyl,trifluoromethyl, pentafluoroethyl, heptafluoropropyl,difluorochloromethyl, dichlorofluoromethyl, difluoroethyl,difluoropropyl and the like.

As used herein, the term “haloalkoxy” refers to radicals wherein one ormore of the hydrogen atoms of the alkoxy groups are substituted with oneor more halogens. Representative examples of “haloalkoxy” groupsinclude, but not limited to, difluoromethoxy (—OCHF₂), trifluoromethoxy(—OCF₃) or trifluoroethoxy (—OCH₂CF₃).

As used herein, the term “aryl” alone or in combination with otherterm(s) means a carbocyclic aromatic system containing one or two ringswherein such rings may be fused. The term “fused” means that the secondring is attached or formed by having two adjacent atoms in common withthe first ring. The term “fused” is equivalent to the term “condensed”.Examples of aryl groups include but are not limited to phenyl, naphthyl,indanyl and the like. Unless otherwise specified, all aryl groupsdescribed herein may be substituted or unsubstituted.

As used herein, “Amino” refers to an —NH₂ group.

As used herein, “alkylamino” refers to amino group wherein one of thehydrogen atom of amino group is replaced with alkyl group.

As used herein, “arylamino” refers to amino group wherein one ofhydrogen atoms is substituted with aryl group.

As used herein, “alkylaminoalkyl” refers to alkyl group substituted with“alkylamino” group defined above.

As used herein, “arylaminoalkyl” refers to arylamino group, as definedabove, substituted with alkyl group.

As used herein, “nitro” refers to an —NO₂ group.

As used herein, “alkylamino” or “cycloalkylamino”, refer to an —N-group,wherein nitrogen atom of said group being attached to alkyl orcycloalkyl respectively. Representative examples of an “Alkylamino” and“Cycloalkylamino” groups include, but are not limited to —NHCH₃ and—NH-cyclopropyl. An amino group can be optionally substituted with oneor more of the suitable groups.

“Aminoalkyl” refers to an alkyl group, as defined above, wherein one ormore of the alkyl group's hydrogen atom has been replaced with an aminogroup as defined above. Representative examples of an aminoalkyl groupinclude, but are not limited to —CH₂NH₂, —CH₂CH₂NH₂, —CH(CH₃)NH₂,—CH₂CH(CH₃)NH₂. An aminoalkyl group can be unsubstituted or substitutedwith one or more suitable groups.

As used herein the term “cycloalkyl” alone or in combination with otherterm(s) means C₃-C₁₀ saturated cyclic hydrocarbon ring. A cycloalkyl maybe a single ring, which typically contains from 3 to 7 carbon ringatoms. Examples of single-ring cycloalkyls include cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Acycloalkyl may alternatively be polycyclic or contain more than onering. Examples of polycyclic cycloalkyls include bridged, fused andspirocyclic carbocyclyls.

As used herein, the term “cyano” refers to —CN group.

As used herein, the term “hydroxy” or “Hydroxyl” refers to —OH group.

As used herein the term “hydroxyalkyl” or “hydroxylalkyl” means alkylsubstituted with one or more hydroxyl groups, wherein the alkyl groupsare as defined above. Examples of “hydroxyalkyl” include but are notlimited to hydroxymethyl, hydroxyethyl, hydroxypropyl, propan-2-ol andthe like.

As used herein, the term “halo” or “halogen” alone or in combinationwith other term(s) means fluorine, chlorine, bromine or iodine.

As used herein, the term “heterocyclyl” includes definitions of“heterocycloalkyl” and “heteroaryl”.

The term “heterocycloalkyl” refers to a non-aromatic, saturated orpartially saturated, monocyclic or polycyclic ring system of 3 to 15members having at least one heteroatom or heterogroup selected from O,N, S, S(O), S(O)₂, NH or C(O) with the remaining ring atoms beingindependently selected from the group consisting of carbon, oxygen,nitrogen and sulfur. Examples of “Heterocycloalkyl” include, but are notlimited to azetidinyl, oxetanyl, imidazolidinyl, pyrrolidinyl,oxazolidinyl, thiazolidinyl, pyrazolidinyl, tetrahydrofuranyl,piperidinyl, piperazinyl, tetrahydropyranyl, morpholinyl,thiomorpholinyl, 1,4-dioxanyl, dioxidothiomorpholinyl, oxapiperazinyl,oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl,tetrahydrothiophenyl, dihydropyranyl, indolinyl, indolinylmethyl,azepanyl, 2-aza-bicyclo[2.2.2]octanyl, azocinyl, chromanyl, xanthenyland N-oxides thereof. Attachment of a heterocycloalkyl substituent canoccur via either a carbon atom or a heteroatom. A heterocycloalkyl groupcan be optionally substituted with one or more suitable groups by one ormore aforesaid groups. Preferably “heterocycloalkyl” refers to 4- to7-membered ring selected from the group consisting of azetidinyl,oxetanyl, imidazolidinyl, pyrrolidinyl, oxazolidinyl, thiazolidinyl,pyrazolidinyl, tetrahydrofuranyl, piperidinyl, piperazinyl,tetrahydropyranyl, morpholinyl, thiomorpholinyl, 1,4-dioxanyl, azepanyland N-oxides thereof. More preferably, “heterocycloalkyl” includesazetidinyl, pyrrolidinyl, morpholinyl, piperidinyl or azepanyl. Allheterocycloalkyl are optionally substituted by one or more aforesaidgroups.

The term “heteroaryl” refers to an aromatic heterocyclic ring systemcontaining 5 to 20 ring atoms, suitably 5 to 10 ring atoms, which may bea single ring (monocyclic) or multiple rings (bicyclic, tricyclic orpolycyclic) fused together or linked covalently. Preferably,“heteroaryl” is a 5- to 6-membered ring. The rings may contain from 1 to4 heteroatoms selected from N, O and S, wherein the N or S atom isoptionally oxidized, or the N atom is optionally quarternized. Anysuitable ring position of the heteroaryl moiety may be covalently linkedto the defined chemical structure.

Examples of heteroaryl include, but are not limited to: furanyl,thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl,isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl,triazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, benzoxazolyl,benzisoxazolyl; benzothiazolyl, benzofuranyl, benzothienyl,benzotriazinyl, phthalazinyl, thianthrene, dibenzofuranyl,dibenzothienyl, benzimidazolyl, indolyl, isoindolyl, indazolyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, purinyl,pteridinyl, 9H-carbazolyl, α-carboline, indolizinyl, benzoisothiazolyl,benzoxazolyl, pyrrolopyridyl, furopyridinyl, purinyl, benzothiadiazolyl,benzooxadiazolyl, benzotriazolyl, benzotriadiazolyl, carbazolyl,dibenzothienyl, acridinyl and the like. Preferably “heteroaryl” refersto 5- to 6-membered ring selected from the group consisting of furanyl,thiophene, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, cinnolinyl,isoxazolyl, thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl,triazolyl, pyridyl, pyrimidinyl, pyrazinyl and pyridazinyl. Morepreferably, pyrazolyl, pyridyl, oxazolyl and furanyl. All heteroarylsare optionally substituted by one or more aforesaid groups.

As used herein, the term “including” as well as other forms, such as“include”, “includes” and “included” is not limiting.

The phrase “pharmaceutically acceptable” refers to compounds orcompositions that are physiologically tolerable and do not typicallyproduce allergic or similar untoward reaction, including but not limitedto gastric upset or dizziness when administered to mammal.

The term “pharmaceutically acceptable salt” refers to a product obtainedby reaction of the compound of the present invention with a suitableacid or a base. Pharmaceutically acceptable salts of the compounds ofthis invention include those derived from suitable inorganic bases suchas Li, Na, K, Ca, Mg, Fe, Cu, Al, Zn and Mn salts; Examples ofpharmaceutically acceptable, nontoxic acid addition salts are salts ofan amino group formed with inorganic acids such as hydrochloride,hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate,isonicotinate, acetate, lactate, salicylate, citrate, tartrate,pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate,fumarate, gluconate, glucaronate, saccharate, formate, benzoate,glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate,4-methylbenzenesulfonate or p-toluenesulfonate salts and the like.Certain compounds of the invention (compounds of formula (I)) can formpharmaceutically acceptable salts with various organic bases such aslysine, arginine, guanidine, diethanolamine or metformin. Suitable basesalts include, but are not limited to, aluminum, calcium, lithium,magnesium, potassium, sodium, or zinc, salts.

As used herein, the term “stereoisomer” is a term used for all isomersof individual compounds of formula (I) that differ only in theorientation of their atoms in space. The term stereoisomer includesmirror image isomers (enantiomers) of compound of formula (I), mixturesof mirror image isomers (racemates, racemic mixtures) compound offormula (I), geometric (cis/trans or E/Z, R/S) isomers compound offormula (I) and isomers of compound of formula (I) with more than onechiral center that are not mirror images of one another(diastereoisomers).

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

As used herein, the term “pharmaceutical composition” refers to acomposition(s) containing a therapeutically effective amount of at leastone compound of formula (I) or its pharmaceutically acceptable salt; anda conventional pharmaceutically acceptable carrier.

The pharmaceutical composition(s) of the present invention can beadministered orally, for example in the form of tablets, coated tablets,pills, capsules, granules or elixirs. Administration, however, can alsobe carried out rectally, for example in the form of suppositories, orparenterally, for example intravenously, intramuscularly orsubcutaneously, in the form of injectable sterile solutions orsuspensions, or topically, for example in the form of ointments orcreams or transdermals, in the form of patches, or in other ways, forexample in the form of aerosols or nasal sprays.

The pharmaceutical composition(s) usually contain(s) about 1% to 99%,for example, about 5% to 75%, or from about 10% to about 30% by weightof the compound of formula (I) or pharmaceutically acceptable saltsthereof. The amount of the compound of formula (I) or pharmaceuticallyacceptable salts thereof in the pharmaceutical composition(s) can rangefrom about 1 mg to about 1000 mg or from about 2.5 mg to about 500 mg orfrom about 5 mg to about 250 mg or in any range falling within thebroader range of 1 mg to 1000 mg or higher or lower than the aforementioned range.

As used herein, the term “pharmaceutically acceptable carrier” refers toany of the standard pharmaceutical carriers, such as a phosphatebuffered saline solution, water, emulsions {e.g., such as an oil/wateror water/oil emulsions) and various types of wetting agents. Thecompositions also can include stabilizers and preservatives. Theexamples of carriers, stabilizers and adjuvant are mentioned inliterature like, Martin, Remington's Pharmaceutical Sciences, 15th Ed.,Mack Publ. Co., Easton, Pa. [1975].

The term “treatment”/“treating” means any treatment of a disease in amammal, including: (a) Inhibiting the disease, i.e., slowing orarresting the development of clinical symptoms; and/or (b) Relieving thedisease, i.e., causing the regression of clinical symptoms and/or (c)alleviating or abrogating a disease and/or its attendant symptoms.

As used herein, the term “prevent”, “preventing” and “prevention” referto a method of preventing the onset of a disease and/or its attendantsymptoms or barring a subject from acquiring a disease. As used herein,“prevent”, “preventing” and “prevention” also include delaying the onsetof a disease and/or its attendant symptoms and reducing a subject's riskof acquiring a disease.

As used herein, the term “subject” refers to an animal, preferably amammal and most preferably a human.

As used herein, the term, “therapeutically effective amount” refers toan amount of a compound of formula (I) or a pharmaceutically acceptablesalt or a stereoisomer thereof; or a composition comprising the compoundof formula (I) or a pharmaceutically acceptable salt or a stereoisomerthereof, effective in producing the desired therapeutic response in aparticular patient suffering from a disease or disorder mediated bykinase enzymes, particularly IRAK or IRAK4 enzyme. Particularly, theterm “therapeutically effective amount” includes the amount of thecompound of formula (I) or a pharmaceutically acceptable salt or astereoisomer thereof, when administered, that induces a positivemodification in the disease or disorder to be treated or is sufficientto prevent development of, or alleviate to some extent, one or more ofthe symptoms of the disease or disorder being treated in a subject. Inrespect of the therapeutic amount of the compound, the amount of thecompound used for the treatment of a subject is low enough to avoidundue or severe side effects, within the scope of sound medical judgmentcan also be considered. The therapeutically effective amount of thecompound or composition will be varied with the particular conditionbeing treated, the severity of the condition being treated or prevented,the duration of the treatment, the nature of concurrent therapy, the ageand physical condition of the end user, the specific compound orcomposition employed and the particular pharmaceutically acceptablecarrier utilized.

In one embodiment, the present invention provides the compound offormula (I);

or a pharmaceutically acceptable salt or a stereoisomer thereof;

wherein,

X₁ and X₃ independently are CH or N; X₂ is CR₂ or N; provided one andnot more than one of X₁, X₂ or X₃ is N;

A is O or S;

Y is —CH₂— or O;

Ring Z is aryl or heterocyclyl;

R₁, at each occurrence, is independently halo or optionally substitutedheterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl,halo, hydroxyl, hydroxyalkyl or —NR_(a)R_(b);

R₂ is hydrogen, optionally substituted cycloalkyl, optionallysubstituted aryl, optionally substituted heterocyclyl or —NR_(a)R_(b);wherein the substituent is alkyl, amino, halo or hydroxyl;

R₃, at each occurrence, is alkyl or hydroxyl;

R_(a) and R_(b) are independently hydrogen, alkyl, acyl or heterocyclyl;

‘m’ and ‘n’ are independently 0, 1 or 2;

‘p’ is 0 or 1.

In one embodiment, the compound of formula (I) or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein the group

wherein R₂ are as defined in compound of formula (I).

In another embodiment, the compound of formula (I) or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein the Ring Z is aryl or5- or 6-membered heterocyclyl.

In another embodiment, the compound of formula (I) or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein the Ring Z is phenyl,furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, 1H-tetrazolyl, oxadiazolyl, triazolyl, pyridyl,pyrimidinyl, pyrazinyl, pyridazinyl, oxetanyl, imidazolidinyl,pyrrolidinyl, oxazolidinyl, thiazolidinyl, pyrazolidinyl,tetrahydrofuranyl, piperidinyl, piperazinyl, tetrahydropyranyl,morpholinyl, thiomorpholinyl,1,4-dioxanyl, dioxidothiomorpholinyl,oxapiperazinyl, oxapiperidinyl, tetrahydrofuryl, tetrahydropyranyl,tetrahydrothiophenyl or dihydropyranyl; each of which is optionallysubstituted with alkyl, alkoxy, halo, hydroxyl, hydroxyalkyl or—NR_(a)R_(b); R_(a) and R_(b) are independently are hydrogen, alkyl oracyl.

In another embodiment, the compound of formula (I) or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein the Ring Z is phenyl,oxazolyl, furanyl, thienyl or pyridyl; each of which is optionallysubstituted with one or more R₁.

In another embodiment, the compound of formula (I) or a pharmaceuticallyacceptable salt or a stereoisomer thereof, wherein

wherein R₃ and ‘m’ are defined in compound of formula (I).

In another embodiment, the compound of formula (I) is a compound offormula (IA):

or a pharmaceutically acceptable salt or a stereoisomer thereof;wherein, A, Y, R₁, R₂, R₃, ‘m’, ‘p’ and ‘n’ are same as defined incompound of formula (I).

In another embodiment, the compound of formula (I) is a compound offormula (IB):

or a pharmaceutically acceptable salt or a stereoisomer thereof;wherein, A, Y, R₁, R₂ and ‘n’ are same as defined in compound of formula(I).

In yet another embodiment, the compound of formula (I) is a compound offormula (IC):

or a pharmaceutically acceptable salt or a stereoisomer thereof;wherein, A, Y, R₁, R₂, R₃ and ‘n’ are same as defined compounds offormula (I).

The embodiments below are illustrative of the present invention and arenot intended to limit the claims to the specific embodimentsexemplified.

According to one embodiment, specifically provided are compounds offormula (I) or (IA) or (IB) or (IC), wherein Y is O or CH₂.

According to one embodiment, specifically provided are compounds offormula (I) wherein R₁ is optionally substituted heterocyclyl; whereinthe substituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl,hydroxyalkyl or —NR_(a)R_(b); R_(a) and R_(b) are independentlyhydrogen, alkyl or acyl.

According to one embodiment, specifically provided are compounds offormula (I) wherein R₁ is pyridyl, pyrazolyl, pyrrolidinyl orpiperidinyl; each of which is optionally substituted with alkyl, alkoxy,halo, hydroxyl, hydroxyalkyl or —NR_(a)R_(b); R_(a) and R_(b) areindependently hydrogen or acyl.

According to one embodiment, specifically provided are compounds offormula (I) wherein R₂ is hydrogen.

According to one embodiment, specifically provided are compounds offormula (I) wherein R₂ is optionally substituted cycloalkyl.

According to one embodiment, specifically provided are compounds offormula (I) wherein R₂ is cyclopropyl.

According to one embodiment, specifically provided are compounds offormula (I) wherein R₂ is optionally substituted heterocyclyl; whereinthe substituent is alkyl, amino, halo or hydroxyl.

According to one embodiment, specifically provided are compounds offormula (I) wherein R₂ is piperidinyl, pyrrolidinyl, morpholinyl,piperazinyl, azetidinyl, pyrazolyl, furanyl, pyridyl, azepanyl orazabicyclo[3.2.1]octanyl; wherein the substituent is alkyl, amino, haloor hydroxyl.

According to one embodiment, specifically provided are compounds offormula (I) wherein R₂ is optionally substituted aryl; wherein thesubstituent is halo.

According to one embodiment, specifically provided are compounds offormula (I) wherein R₂ is optionally substituted phenyl; wherein thesubstituent is fluoro.

According to one embodiment, specifically provided are compounds offormula (I) wherein R₂ is —NR_(a)R_(b); wherein R_(a) and R_(b) areindependently hydrogen or heterocyclyl.

According to one embodiment, specifically provided are compounds offormula (I) wherein R₂ is —NR_(a)R_(b); wherein R_(a) and R_(b) areindependently hydrogen or pyrrolidinyl.

According to one embodiment, specifically provided are compounds offormula (IA) wherein A is O or S; Y is —CH₂— or O; R₁ is halo, pyridyl,pyrazolyl, pyrrolidinyl each of which is optionally substituted withalkyl, alkoxy, halo, hydroxyl, hydroxyalkyl or —NR_(a)R_(b); R₂ ishydrogen, optionally substituted cycloalkyl, optionally substitutedaryl, optionally substituted heterocyclyl or —NR_(a)R_(b); wherein thesubstituent is alkyl, amino, halo or hydroxyl; R_(a) and R_(b) areindependently hydrogen or alkyl.

According to one embodiment, specifically provided are compounds offormula (IB) wherein A is O or S; Y is —CH₂— or O; R₁ is pyridyl,pyrazolyl, pyrrolidinyl; each of which is optionally substituted withalkyl, hydroxyl, hydroxyalkyl or —NR_(a)R_(b); R_(a) and R_(b) areindependently hydrogen; R₂ is hydrogen, optionally substitutedcycloalkyl, optionally substituted aryl, optionally substitutedheterocyclyl or —NR_(a)R_(b); wherein the substituent is alkyl, amino,halo or hydroxyl; R_(a) and R_(b) are independently hydrogen, alkyl,acyl or heterocyclyl.

According to one embodiment, specifically provided are compounds offormula (IA), (IB) and (IC), wherein ‘n’ is 0, 1 or 2.

According to one embodiment, specifically provided are compounds offormula (IA) and (IB), wherein ‘p’ is 0 or 1.

According to one embodiment, specifically provided are compounds offormula (IA) and (IB), wherein ‘m’ is 0 or 2.

In yet further embodiment, the present invention relates to a processfor preparing bicyclic heterocyclyl derivatives of formula (I).

In yet further embodiment, the present invention relates to apharmaceutical composition, comprising at least one compound of formula(I), or a pharmaceutically acceptable salt or a stereoisomer thereof anda pharmaceutically acceptable carrier or excipient.

In further embodiment, the present invention provides a method oftreating IRAK4 mediated disorders or diseases or condition in a subjectcomprising administering a therapeutically effective amount of acompound of formula (I).

In further embodiment, the IRAK4-mediated disorder or disease orcondition is selected from the group consisting of cancer, aninflammatory disorder, an autoimmune disease, metabolic disorder, ahereditary disorder, a hormone-related disease, immunodeficiencydisorders, a condition associated with cell death, a destructive bonedisorder, thrombin-induced platelet aggregation, liver disease and acardiovascular disorder.

In further embodiment, the cancer is selected the group consisting of asolid tumor, benign or malignant tumor, carcinoma of the brain, kidney,liver, stomach, vagina, ovaries, gastric tumors, breast, bladder colon,prostate, pancreas, lung, cervix, testis, skin, bone or thyroid;sarcoma, glioblastomas, neuroblastomas, multiple myeloma,gastrointestinal cancer, a tumor of the neck and head, an epidermalhyperproliferation, psoriasis, prostate hyperplasia, a neoplasia,adenoma, adenocarcinoma, keratoacanthoma, epidermoid carcinoma, largecell carcinoma, non-small-cell lung carcinoma, lymphomas, Hodgkins andNon-Hodgkins, a mammary carcinoma, follicular carcinoma, papillarycarcinoma, seminoma, melanoma; hematological malignancies selected fromleukemia, diffuse large B-cell lymphoma (DLBCL), activated B-cell-likeDLBCL, chronic lymphocytic leukemia (CLL), chronic lymphocytic lymphoma,primary effusion lymphoma, Burkitt lymphoma/leukemia, acute lymphocyticleukemia, B-cell pro lymphocytic leukemia, lymphoplasmacytic lymphoma,Waldenstrom's macroglobulnemia (WM), splenic marginal zone lymphoma,intravascular large B-cell lymphoma, plasmacytoma and multiple myeloma.

In further embodiment, the inflammatory disorder is selected from thegroup consisting of ocular allergy, conjunctivitis, keratoconjunctivitissicca, vernal conjunctivitis, allergic rhinitis, autoimmunehematological disorders (e.g. hemolytic anemia, aplastic anemia, purered cell anemia and idiopathic thrombocytopenia), systemic lupuserythematosus, rheumatoid arthritis, polychondritis, scleroderma,Wegener granulamatosis, dermatomyositis, chronic active hepatitis,myasthenia gravis, Steven-Johnson syndrome, idiopathic sprue, autoimmuneinflammatory bowel disease (e.g. ulcerative colitis and Crohn'sdisease), irritable bowel syndrome, celiac disease, periodontitis,hyaline membrane disease, kidney disease, glomerular disease, alcoholicliver disease, multiple sclerosis, endocrine opthalmopathy, Grave'sdisease, sarcoidosis, alveolitis, chronic hypersensitivity pneumonitis,primary biliary cirrhosis, uveitis (anterior and posterior), Sjogren'ssyndrome, interstitial lung fibrosis, psoriatic arthritis, systemicjuvenile idiopathic arthritis, nephritis, vasculitis, diverticulitis,interstitial cystitis, glomerulonephritis (e.g. including idiopathicnephrotic syndrome or minimal change nephropathy), chronic granulomatousdisease, endometriosis, leptospirosis renal disease, glaucoma, retinaldisease, headache, pain, complex regional pain syndrome, cardiachypertrophy, muscle wasting, catabolic disorders, obesity, fetal growthretardation, hypercholesterolemia, heart disease, chronic heart failure,mesothelioma, anhidrotic ecodermal dysplasia, Behcet's disease,incontinentia pigmenti, Paget's disease, pancreatitis, hereditaryperiodic fever syndrome, asthma, acute lung injury, acute respiratorydistress syndrome, eosinophilia, hypersensitivities, anaphylaxis,fibrositis, gastritis, gastroenteritis, nasal sinusitis, ocular allergy,silica induced diseases, chronic obstructive pulmonary disease (COPD),cystic fibrosis, acid-induced lung injury, pulmonary hypertension,polyneuropathy, cataracts, muscle inflammation in conjunction withsystemic sclerosis, inclusion body myositis, myasthenia gravis,thyroiditis, Addison's disease, lichen planus, appendicitis, atopicdermatitis, asthma, allergy, blepharitis, bronchiolitis, bronchitis,bursitis, cervicitis, cholangitis, cholecystitis, chronic graftrejection, colitis, conjunctivitis, cystitis, dacryoadenitis,dermatitis, juvenile rheumatoid arthritis, dermatomyositis,encephalitis, endocarditis, endometritis, enteritis, enterocolitis,epicondylitis, epididymitis, fasciitis, Henoch-Schonlein purpura,hepatitis, hidradenitis suppurativa, immunoglobulin A nephropathy,interstitial lung disease, laryngitis, mastitis, meningitis, myelitismyocarditis, myositis, nephritis, oophoritis, orchitis, osteitis,otitis, pancreatitis, parotitis, pericarditis, peritonitis, pharyngitis,pleuritis, phlebitis, pneumonitis, pneumonia, polymyositis, proctitis,prostatitis, pyelonephritis, rhinitis, salpingitis, sinusitis,stomatitis, synovitis, tendonitis, tonsillitis, ulcerative colitis,vasculitis, vulvitis, alopecia areata, erythema multiforma, dermatitisherpetiformis, scleroderma, vitiligo, hypersensitivity angiitis,urticaria, bullous pemphigoid, pemphigus vulgaris, pemphigus foliaceus,paraneoplastic pemphigus, epidermolysis bullosa acquisita, acute andchronic gout, chronic gouty arthritis, psoriasis, psoriatic arthritis,rheumatoid arthritis, Cryopyrin Associated Periodic Syndrome (CAPS) andosteoarthritis.

In further embodiment, the present invention provides a compound or apharmaceutically acceptable salt or a stereoisomer thereof, for use forthe treatment of a cancer, an inflammatory disorder, a an autoimmunedisease, metabolic disorder, a hereditary disorder, a hormone-relateddisease, immunodeficiency disorders, a condition associated with celldeath, a destructive bone disorder, thrombin-induced plateletaggregation, liver disease and a cardiovascular disorder.

In further embodiment, the present invention relates to a use of thecompound of formula (I), or a pharmaceutically acceptable salt or astereoisomer thereof, in the manufacture of a medicament for thetreatment of a cancer, an inflammatory disorder, a an autoimmunedisease, metabolic disorder, a hereditary disorder, a hormone-relateddisease, immunodeficiency disorders, a condition associated with celldeath, a destructive bone disorder, thrombin-induced plateletaggregation, liver disease and a cardiovascular disorder.

In further embodiment, the neurodegenerative disease is selected fromthe group consisting of Alzheimer's disease, Parkinson's disease,amyotrophic lateral sclerosis, Huntington's disease, cerebral ischemiaand neurodegenerative disease caused by traumatic injury, glutamateneurotoxicity, hypoxia, epilepsy and graft versus host disease.

An embodiment of the present invention provides the IRAK4 inhibitorcompounds according to formula (I) may be prepared from readilyavailable starting materials using the following general methods andprocedures. It will be appreciated that where typical or preferredexperimental conditions (i.e. reaction temperatures, time, moles ofreagents, solvents etc.) are given, other experimental conditions canalso be used unless otherwise stated. Optimum reaction conditions mayvary with the particular reactants or solvents used, but such conditionscan be determined by the person skilled in the art, using routineoptimisation procedures. Moreover, by utilizing the procedures describedin detail, one of ordinary skill in the art can prepare additionalcompounds of the present invention claimed herein. All temperatures arein degrees Celsius (° C.) unless otherwise noted.

In a further embodiment, the compounds of the present invention can alsocontain unnatural proportions of atomic isotopes at one or more of theatoms that constitute such compounds. For example, the present inventionalso embraces isotopically-labeled variants of the present inventionwhich are identical to those recited herein, but for the fact that oneor more atoms of the compounds are replaced by an atom having the atomicmass or mass number different from the predominant atomic mass or massnumber usually found in nature for the atom. All isotopes of anyparticular atom or element as specified are contemplated within thescope of the compounds of the invention and their uses. Exemplaryisotopes that can be incorporated in to compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine, chlorine and iodine, such as ²H (“D”), ³H, ¹¹C, ¹³C,¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³²P, ³³P, ³⁵S, ¹⁸F, ³⁶Cl, ¹²³I and ¹²⁵I.Isotopically labeled compounds of the present inventions can generallybe prepared by following procedures analogous to those disclosed in theSchemes and/or in the Examples herein below, by substituting anisotopically labeled reagent for a non-isotopically labeled reagent.

The MS (Mass Spectral) data provided in the examples were obtained usingthe equipments—

API 2000 LC/MS/MS/Triplequad,

Agilent (1100) Technologies/LC/MS/DVL/Singlequad and

Shimadzu LCMS-2020/Singlequad.

The NMR data provided in the examples were obtained using theequipment—′¹H-NMR: Varian −300, 400 and 600 MHz.

The abbreviations used in the entire specification may be summarizedherein below with their particular meaning.

° C. (degree Celsius); 6 (delta); % (percentage); Ac₂O (Aceticanhydride); (Boc)₂O (boc anhydride); bs (Broad singlet); CDCl₃(Deuteriated chloroform); CH₂Cl₂/DCM (Dichloromethane); DMF (Dimethylformamide); DMSO (Dimethyl sulphoxide); DIPEA/DIEA (N, N-Diisopropylethylamine); DAST (Diethylaminosulfur trifluoride); DMAP (Dimethyl aminopyridine); DMSO-d₆ (Deuteriated DMSO); d (Doublet); dd (Doublet ofdoublet); EDCI. HCl (1-(3-Dimethyl aminopropyl)-3-carbodiimidehydrochloride); EtOAc (Ethyl acetate); EtOH (Ethanol); Fe (Iron powder);g (gram); H or H₂ (Hydrogen); H₂O (Water); HATU(1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate); HOBt (1-Hydroxy benzotriazole); H₂SO₄(Sulphuric acid); HCl (Hydrochloric acid or Hydrochloride salt); h or hr(Hours); Hz (Hertz); HPLC (High-performance liquid chromatography); J(Coupling constant); K₂CO₃ (Potassium carbonate); KOAc (PotassiumAcetate); KNO₃ (Potassium nitrate); LiOH (Lithium hydroxide); NaHMDS(Sodiumbis(trimethylsilyl)amide); MeOH/CH₃OH (Methanol); mmol(Millimol); M (Molar); ml (Millilitre); mg (Milli gram); m (Multiplet);mm (Millimeter); MHz (Megahertz); MS (ES) (Mass spectroscopy-electrospray); min (Minutes); NaH (Sodium hydride); NaHCO₃ (Sodiumbicarbonate); Na₂SO₄ (Sodium sulphate); NH₄Cl (Ammonium Chloride); N₂(Nitrogen); NMR (Nuclear magnetic resonance spectroscopy); Pd(PPh₃)₂Cl₂(Bis(triphenylphosphine)palladium(II) dichloride); Pd(OAc)₂ (Palladiumdiacetate); Pd(dppf)Cl₂ (1,1′-Bis(diphenylphosphino)ferrocene)palladium(II) dichloride; RT (Room Temperature); s (Singlet); TBAF(Tetra-n-butylammonium fluoride); TEA (Triethylamine); TFA(Trifluoroaceticacid); TLC (Thin Layer Chromatography); THF(Tetrahydrofuran); TFA (Trifluoro acetic acid); t (Triplet); and Zn(CN)₂(Zinc Cyanide).

Compounds of this invention may be made by synthetic chemical processes,examples of which are shown herein. It is meant to be understood thatthe order of the steps in the processes may be varied, that reagents,solvents and reaction conditions may be substituted for thosespecifically mentioned and that vulnerable moieties may be protected anddeprotected, as necessary.

A general approach for the synthesis of some of the compounds of generalformula (ix) is depicted in below schemes. As used herein the belowschemes the terms Z, Y, R₁, R₂, R₃, m, n and p represents all thepossible substitutions as disclosed in formula (I).

The first general approach for the synthesis of compounds of generalformula (ix) is depicted in scheme-1. Compound of formula (ii) can beobtained from compound of formula (i) by reacting with potassium ethylxanthate in appropriate solvent like pyridine at a higher temperature.Compound of formula (ii) on alkylation with methyl iodide using baselike potassium carbonate can give compound of formula (iii) can besubjected to nucleophilic displacement with suitable nucleophile to givecompound of formula (iv). Compound of formula (iv) on nitration can givecompound of formula (v). Compound of formula (v) can be subjected toSuzuki reaction to give compound of formula (vi) which on reduction withsuitable reducing reagents like Zn and ammonium chloride can givecompound of formula (vii). Compound of formula vii can be subjected toAmide coupling with a suitable acid of compound of formula (viii) byusing a standard amide coupling reagent known in the literature to givecompound of formula (ix).

INTERMEDIATES Intermediate 1: Synthesis of tert-butyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate

Step 1: Preparation of tert-butyl (5-bromopyridin-2-yl)carbamate

To a solution of 5-bromopyridin-2-amine (5.0 g, 28.901 mmol) in DCM (50mL) was added DMAP (5.28 g, 43.351 mmol) and Boc anhydride (7.56 g,34.682 mmol) and stirred at RT for overnight. The solvent was distilledout and purified by 60-120 silica gel column chromatography using 30%ethyl acetate in hexane as eluent to obtain the title compound (5.5 g,69.62%).

¹HNMR (CDCl₃, 300 MHz): δ 8.327-8.320 (d, 1H), 8.10 (bs, 1H), 7.92-7.89(d, 1H), 7.76-7.73 (dd, 1H), 1.55 (s, 9H). LCMS: m/z: 217.0 (M-Boc)⁺.

Step 2: Preparation of tert-butyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate

In a sealed tube, tert-butyl (5-bromopyridin-2-yl)carbamate (5.0 g,0.18315 mmol),4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (6.02 g,23.8 mmol) and potassium acetate (5.38 mg, 54.945 mmol) were taken in1,4-dioxane (50 mL) and purged argon for 10 min. Added Pd(dppf)Cl₂ (669mg, 0.915 mmol) and heated at 100° C. for 2 h. The solvent was distilledout and purified by 60-120 silica gel column chromatography using 40%ethyl acetate in hexane as eluent to obtain the title compound (5.0 g,85.32%).

Intermediate 2: Synthesis of tert-butyl(6-carbamoyl-[2,3′-bipyridin]-6′-yl)carbamate

Step 1: Preparation of 6-bromopicolinamide

Using the same reaction conditions as described in step 6 of example 1,6-bromopicolinic acid (2 g, 9.9 mmol) was coupled with ammonium chloride(787 mg, 14.851 mmol) using EDCI.HCl (2.8 g, 14.851 mmol), HOBt (2.0 g,14.851 mmol) and DIPEA (3.8 g, 29.750 mmol) in DMF (10 mL) to get thecrude product. The resultant crude was purified using 60-120 silica-gelcolumn chromatography and compound was eluted using 50% ethyl acetate inhexane as eluent to afford the title compound (2.0 g, 100%).

¹HNMR (CDCl₃, 300 MHz): δ 8.18-8.16 (d, 1H), 7.7.63-7.5656-7.63 (m, 2H),5.80-5.60 (bs, 2H).

Step 2: Preparation of tert-butyl(6-carbamoyl-[2,3′-bipyridin]-6′-yl)carbamate

Using the same reaction conditions as described in step 7 of example 1,6-bromopicolinamide (2.0 g, 9.95 mmol) was coupled with tert-butyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate(intermediate 1) (3.8 g, 11.94 mmol) using sodium carbonate (3.2 g,29.85 mmol) and Pd(PPh₃)₂Cl₂ (363 mg, 0.5 mmol) in 1,2-dimethoxyethane(10 mL) to get the crude product. The resultant crude was purified by60-120 silica gel column chromatography using 2% methanol in DCM aseluent to obtain the title compound (2.8 g, 90.3%).

¹HNMR (CDCl₃, 300 MHz): δ 8.908-8.901 (d, 1H), 8.30-8.26 (dd, 1H),8.18-8.16 (d, 1H), 8.09-8.06 (d, 1H), 7.97-7.68 (m, 3H), 7.26 (s, 1H),5.70-5.60 (s, 1H), 1.55 (s, 9H). LCMS: m/z: 259.1 (de-t-butyl).

Intermediate 3: Synthesis of6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid

Step 1: Preparation of methyl6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinate

Using the same reaction conditions as described in step 7 of example 1,methyl 6-bromopicolinate (900 mg, 4.166 mmol) was coupled with1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(1.39 g, 5 mmol) using sodium carbonate (1.324 g, 12.49 mmol) andPd(PPh₃)₂Cl₂ (339 mg, 0.416 mmol) in 1,2-dimethoxyethane (10 mL) to getthe crude product. The resultant crude was purified by 60-120 silica gelcolumn chromatography using 30% ethyl acetate in hexane as eluent toobtain the title compound (450 mg, 38%). LCMS: m/z: 288.1 (M+1)⁺.

Step 2: Preparation of6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid

A solution of methyl6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinate (450 mg,1.567 mmol) and lithium hydroxide (500 mg, 7.839 mmol) in THFmethanol/H₂O (10 mL/4 ml/1 ml) was stirred at RT for 2 hrs. The reactionmixture was acidified with citric acid and extracted with DCM (2×100 mL)dried over sodium sulphate and distilled out the solvent to get thetitle compound (300 mg, 70%). LCMS: m/z: 274.3 (M+1)⁺.

Intermediate 4: Synthesis of 6-(1-methyl-1H-pyrazol-4-yl)picolinic acid

Step 1: Preparation of methyl 6-(1-methyl-1H-pyrazol-4-yl)picolinate

Using the same reaction conditions as described in step 7 of example 1,methyl 6-bromopicolinate (3.5 g, 16.28 mmol) was coupled with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(4.06 g, 19.53 mmol) using sodium carbonate (5.177 g, 48.846 mmol) andPd(dppf)Cl₂ (1.328 g, 1.628 mmol) in 1,2-dimethoxyethane (20 mL) to getthe crude product. The resultant crude was purified by 60-120 silica gelcolumn chromatography using 30% ethyl acetate in hexane as eluent toobtain the title compound (1.2 g, 33.9%). LCMS: m/z: 218.2 (M+1)⁺.

Step 2: Preparation of 6-(1-methyl-1H-pyrazol-4-yl)picolinic acid

Using the same reaction conditions as described in step 2 ofintermediate 5, 6-(1-methyl-1H-pyrazol-4-yl)picolinic acid (1.2 g, 5.529mmol) was hydrolysed using lithium hydroxide (696 mg, 16.58 mmol) inTHF/methanol (8/2 mL) at RT for 2 h to obtain the title compound (900mg, 80.3%). LCMS: m/z: 204.0 (M+1)⁺.

Intermediate 5: Synthesis of3-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoicacid

Step 1: Preparation of methyl3-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoate

Using the same reaction conditions as described in step 4 of example 12,methyl 3-bromo-5-fluorobenzoate (100 mg, 0.429 mmol) was coupled withtert-butyl (piperidin-4-ylmethyl)carbamate (110 mg, 0.515 mmol) usingcesium carbonate (209 mg, 0.643 mmol), xantphos (14 mg, 0.025 mmol) andPd₂(dba)₃ (8 mg, 0.0085 mmol) in toluene (5 mL) to get the crudeproduct. The resultant crude was purified by 60-120 silica gel columnchromatography using 2% methanol in DCM as eluent to obtain the titlecompound (110 mg, 70.06%). LCMS: 94.13%, m/z=367.5 (M+1)⁺.

Step 2: Preparation of3-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoicacid

A solution of methyl3-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoate(110 mg, 0.02 mmol), lithium hydroxide (5 mg, 0.104 mmol), methanol (3mL), THF (2 mL) and water (1 mL) was stirred at RT for 1 h., acidifiedwith 2N HCl, distilled the solvent and filtered the solid to get thecrude product. This was then purified by prep HPLC to obtain the titlecompound (105 mg, 100%). LCMS: m/z: 353.4 (M+1)⁺.

Intermediate 6: Synthesis of2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoicacid

Step 1: Preparation of methyl2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoate

Using the same reaction conditions as described in step 1 of example 11,methyl 2,5-difluorobenzoate (1 g, 4.6 mmol), was coupled with tert-butyl(piperidin-4-ylmethyl)carbamate (803 mg, 4.6 mmol) using potassiumcarbonate (1.289 mg, 9.3 mmol), in DMF (10 mL) at 90° C. overnight toget the crude product. The resultant crude was purified by 60-120 silicagel column chromatography using ethyl acetate in hexane as eluent toobtain the title compound (300 mg, 20%).

¹HNMR (DMSO-d₆, 400 MHz): δ 7.38-7.28 (m, 2H), 7.16-7.12 (m, 1H),6.90-6.85 (t, 1H), 3.80 (s, 3H), 3.13-3.10 (d, 2H), 2.87-2.84 (m, 2H),2.64-2.58 (t, 2H), 1.67-1.64 (d, 2H), 1.40 (s, 9H), 1.26-1.09 (m, 2H).LCMS: m/z: 367.3 (M+1)⁺.

Step 2: Preparation of2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoicacid

Using the same reaction conditions as described in step 2 ofintermediate 5, methyl2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoate(300 mg, 0.819 mmol), was hydrolysed using lithium hydroxide (172 mg,4.098 mmol) in THF/methanol/H₂O (5 mL/1 ml/0.5 ml) at RT for 2 h toobtain the title compound (220 mg, 77%).

¹HNMR (DMSO-d₆, 300 MHz): δ 7.86-7.83 (m, 1H), 7.74-7.70 (m, 1H),7.55-7.54 (m, 1H), 7.01 (bs, 1H), 3.11-3.08 (m, 4H), 2.93-2.89 (t, 2H),1.87-1.83 (d, 2H), 1.70-1.60 (bs, 1H), 1.40 (s, 9H), 1.35-1.30 (m, 2H).LCMS: m/z: 353.4 (M+1)⁺.

Intermediate 7: Synthesis of2-(6-methoxypyridin-3-yl)oxazole-4-carboxylic acid

Step 1: Preparation of ethyl2-(6-fluoropyridin-3-yl)oxazole-4-carboxylate

Using the same reaction conditions as described in step 7 of example 1,2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (200mg, 1.41 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (298mg, 1.70 mmol) using sodium carbonate (451 mg, 4.25 mmol) and Pd(PPh₃)₄(289 mg, 0.332 mmol) in 1,2-dimethoxyethane/water (15/3 mL) to get thecrude product. The resultant crude was purified by 60-120 silica gelcolumn chromatography using 20% ethyl acetate in hexane as eluent toobtain the title compound (200 mg, 59.8%).

Step 2: Preparation of 2-(6-methoxypyridin-3-yl)oxazole-4-carboxylicacid

Using the same reaction conditions as described in step 2 ofintermediate 5, ethyl 2-(6-fluoropyridin-3-yl)oxazole-4-carboxylate (300mg, 0.127 mmol) was hydrolysed using lithium hydroxide (160 mg, 3.91mmol) in THF/methanol/water (5/1/2 mL) at RT for 2 h to obtain the titlecompound (160 mg, 57.3%).

¹HNMR (DMSO-d₆, 300 MHz): δ 13.5-12.5 (bs, 1H), 8.85 (s, 1H), 8.80-8.79(d, 1H), 8.26-8.23 (dd, 1H), 7.02-6.99 (dd, 1H), 3.95 (s, 3H). LCMS:m/z=221.1 (M+1)⁺.

Intermediate 8: Synthesis of2-(2-methylpyridin-3-yl)oxazole-4-carboxylic acid

Step 1: Preparation of ethyl2-(2-methylpyridin-3-yl)oxazole-4-carboxylate

Using the same reaction conditions as described in step 7 of example 1,2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (1 g,7.09 mmol) was coupled with ethyl 2-chlorooxazole-4-carboxylate (1.86 g,0.851 mmol) using sodium carbonate (2.25 g, 21.2 mmol) and Pd(dppf)Cl₂(289 mg, 0.332 mmol) in 1,2-dimethoxyethane/water (30/6 mL) to get thecrude product. The resultant crude was purified by 60-120 silica gelcolumn chromatography using 20% ethyl acetate in hexane as eluent toobtain the title compound (1 g, 59.8%).

Step 2: Preparation of 2-(2-methylpyridin-3-yl)oxazole-4-carboxylic acid

Using the same reaction conditions as described in step 2 ofintermediate 5, ethyl 2-(2-methylpyridin-3-yl)oxazole-4-carboxylate (1g, 4.3 mmol) was hydrolysed using lithium hydroxide (542 mg, 12.9 mmol)in THF/water (25/4 mL) at RT for 2 h to obtain the title compound (550mg, 62.5%).

¹HNMR (DMSO-d₆, 400 MHz): δ 13.3 (s, 1H), 8.96 (s, 1H), 8.64-8.62 (dd,1H), 8.32-8.03 (dd, 1H), 7.47-7.44 (q, 1H), 2.86 (s, 3H). LCMS:m/z=205.0 (M+1)⁺.

Intermediate 9: Synthesis of2-(2-hydroxypyridin-3-yl)oxazole-4-carboxylic acid

Step 1: Preparation of ethyl2-(2-fluoropyridin-3-yl)oxazole-4-carboxylate

Using the same reaction conditions as described in step 7 of example 1,(2-fluoropyridin-3-yl)boronic acid (400 mg, 2.83 mmol) was coupled withethyl 2-chlorooxazole-4-carboxylate (596 mg, 3.40 mmol) using sodiumcarbonate (902 mg, 8.51 mmol) and Pd(dppf)Cl₂ (115 mg, 0.141 mmol) in1,2-dimethoxyethane/water (25/4 mL) to get the crude product. Theresultant crude was purified by 60-120 silica gel column chromatographyusing 30% ethyl acetate in hexane as eluent to obtain the title compound(400 mg, 60.6%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.11 (s, 1H), 8.64-8.59 (m, 1H), 8.48-8.47(d, 1H), 7.62-7.59 (m, 1H), 4.38-4.33 (q, 2H), 1.35-1.32 (t, 3H).

Step 2: Preparation of 2-(2-hydroxypyridin-3-yl)oxazole-4-carboxylicacid

Using the same reaction conditions as described in step 2 ofintermediate 5, ethyl 2-(2-fluoropyridin-3-yl)oxazole-4-carboxylate (400mg, 1.69 mmol) was hydrolysed using lithium hydroxide (213 mg, 5.07mmol) in THF/water (10/2 mL) at RT for 2 h to obtain the title compound(250 mg, 71.6%).

¹HNMR (DMSO-d₆, 400 MHz): δ 13.3-12.9 (bs, 1H), 12.4-12.2 (s, 1H), 8.81(s, 1H), 8.20-8.17 (dd, 1H), 7.68-7.66 (dd, 1H), 6.41-6.37 (t, 1H).LCMS: m/z=207.1 (M+1)⁺.

Intermediate 10: Synthesis of2-(2-hydroxypyridin-5-yl)oxazole-4-carboxylic acid

Using the same reaction conditions as described in step 2 ofintermediate 5, ethyl 2-(6-fluoropyridin-3-yl)oxazole-4-carboxylate(product of step 1 of intermediate 7) (400 mg, 1.69 mmol) was hydrolysedusing lithium hydroxide (400 mg, 10.3 mmol) in THF/water (2/2 mL) at RTfor 2 h to obtain the crude title compound (300 mg). LCMS: m/z=207.1(M+1)⁺.

Intermediate 11: Synthesis of2-(2-methoxypyridin-4-yl)oxazole-4-carboxylic acid

The title compound was prepared by using the similar conditions andreagents according to the procedure described in the synthesis ofIntermediate-7.

¹HNMR (DMSO-d₆, 300 MHz): δ 8.38 (s, 1H) 8.34-8.32 (d, 1H) 7.53-7.52 (d,1H) 7.33 (s, 1H) 3.91 (s, 3H). LCMS: m/z=221.1 (M+1)′.

The below intermediates were prepared by using appropriate reagentsaccording to the above protocol depicted in Intermediate 8.

Intermediate No. Structure Characterization Data 12

¹HNMR (DMSO-d₆, 300 MHz): δ13.3 (bs, 1H) 8.97 (s, 1H) 8.64 (s, 1H)8.58-8.57 (d, 1H) 7.86- 7.84 (d, 1H) 2.62 (s, 3H). LCMS: m/z = 205.0(M + 1)⁺, HPLC: 98.44%. 13

¹HNMR (DMSO-d₆, 300 MHz): δ13.3 (bs, 1H) 9.03 (s, 1H) 8.88 (s, 1H)8.24-8.20 (d, 1H) 7.46- 7.43 (d, 1H) 2.54 (s, 3H). LCMS: m/z = 205.1(M + 1)⁺, HPLC: 97.33%.

Intermediate 14: Synthesis of(S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylicacid

Step 1: Preparation of ethyl(S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylate

The mixture of ethyl 2-chlorooxazole-4-carboxylate (100 mg, 0.5698mmol), tert-butyl (S)-pyrrolidin-3-ylcarbamate (127 mg, 0.6837 mmol),DIPEA (0.284 mL, 1.4245 mmol) and DMF (5 mL) were heated at 120° C. for2 h. The reaction mass was quenched with ice water and extracted withDCM. The solvent was distilled out to get the title compound (170 mg,91.89%). LCMS: m/z=270.1 (M−t-butyl+1)⁺.

Step 2: Preparation of(S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylicacid

Using the same reaction conditions as described in step 2 ofintermediate 5, ethyl(S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylate(170 mg, 0.5224 mmol) was hydrolysed using lithium hydroxide (33 mg,0.7837 mmol) in THF/methanol/water (10/1/2 mL) at RT for 12 h to obtainthe title compound (150 mg, 96.77%). LCMS: m/z=242.0 (M−t-butyl+1)⁺.

Intermediate 15: Synthesis of(S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylicacid

Step 1: Preparation of ethyl(S)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxylate

Using the same reaction conditions as described in step 1 ofintermediate 14, ethyl 2-chlorooxazole-4-carboxylate (500 mg, 2.8490mmol) was reacted with (S)-pyrrolidin-3-ol (298 mg, 3.4188 mmol) using,sodium carbonate (453 mg, 4.2735 mmol) in DMF (10 mL) to get the titlecompound (535 mg, 83.07%).

LCMS: m/z=227.1 (M+1)⁺.

Step 2: Preparation of ethyl(S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylate

Using the same reaction conditions as described in step 2 of example 41,ethyl(S)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxylate (535 mg,2.3672 mmol) was protected using TBDMS chloride (429 mg, 2.8407 mmol),imidazole (396 mg, 5.8072 mmol) and DMAP (29 mg, 0.2367 mmol) in DMF (5mL) at RT for 2 h to get the crude product. The resultant crude waspurified by 60-120 silica gel column chromatography using 20% ethylacetate in hexane as eluent to obtain the title compound (520 mg,64.5%). LCMS: m/z=341.2 (M+1)⁺.

Step 3: Preparation of(S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylicacid

Using the same reaction conditions as described in step 2 ofintermediate 5, ethyl(S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylate(520 mg, 1.5294 mmol) was hydrolysed using lithium hydroxide (97 mg,2.2941 mmol) in THF/methanol/water (10/5/5 mL) at RT for 2 h to obtainthe title compound (350 mg, 73.37%).

¹HNMR (CDCl₃, 400 MHz): δ 7.88 (s, 1H), 4.55-4.50 (s, 1H), 3.75-3.60 (m,3H), 3.5-3.4 (d, 1H), 2.05-1.90 (m, 2H), 0.9 (s, 9H). LCMS: m/z=313.1(M+1)⁺.

Intermediate 16: Synthesis of2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxylicacid

Step 1: Preparation of ethyl2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxylate

Using the same reaction conditions as described in step 7 of example 1,1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(273 mg, 0.982 mmol) was coupled with ethyl2-chlorooxazole-4-carboxylate (125 mg, 0.892 mmol) using sodiumcarbonate (283 mg, 2.676 mmol) and Pd(dppf)Cl₂ (65 mg, 0.089 mmol) in1,2-dimethoxyethane/water (5/1 mL) to get the crude product. Theresultant crude was purified by 60-120 silica gel column chromatographyusing 20% ethyl acetate in hexane as eluent to obtain the title compound(200 mg, 43.9%). LCMS: m/z=292.3 (M+1)⁺.

Step 2: Preparation of2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxylicacid

Using the same reaction conditions as described in step 2 ofintermediate 5, ethyl2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxylate(200 mg, 0.784 mmol) was hydrolysed using lithium hydroxide (50 mg,1.176 mmol) in THF/methanol/water (5/2/1 mL) at RT for 1 h to obtain thetitle compound (206 mg, 100%). LCMS: m/z=263.9 (M+1)⁺.

Intermediate 17: Synthesis of5-(2-methylpyridin-4-yl)thiophene-2-carboxylic acid

Step 1: Preparation of methyl5-(2-methylpyridin-4-yl)thiophene-2-carboxylate

Using the similar reaction conditions as described in step 7 of example1, methyl 5-bromothiophene-2-carboxylate (460 mg, 2.08 mmol) was coupledwith 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(680 mg, 3.10 mmol) using potassium carbonate (576 mg, 4.17 mmol) TBAB(100 mg, 0.310 mmol) and Pd(dppf)Cl₂ (108 mg, 0.1538 mmol) indioxane/water (10/3 mL) to get the crude product. The resultant crudewas purified by 60-120 silica gel column chromatography using 50% ethylacetate in hexane as eluent to obtain the title compound (552 mg, 91%).LCMS: m/z=234.0 (M+1)⁺.

Step 2: Preparation of 5-(2-methylpyridin-4-yl)thiophene-2-carboxylicacid

Using the same reaction conditions as described in step 2 ofintermediate 5, 5-(2-methylpyridin-4-yl)thiophene-2-carboxylate (550 mg,2.36 mmol) was hydrolysed using lithium hydroxide (200 mg, 4.72 mmol) inTHF/methanol/water (10/5/5 mL) at 50° C. for 15 min to obtain the titlecompound (501 mg, 97%). LCMS: m/z=220.0 (M+1)⁺.

Intermediate 18: Synthesis of 5-(2-methylpyridin-4-yl)furan-2-carboxylicacid

Step 1: Preparation of methyl5-(2-methylpyridin-4-yl)furan-2-carboxylate

Using the similar reaction conditions as described in step 7 of example1, methyl 5-bromofuran-2-carboxylate (214 mg, 1.0406 mmol) was coupledwith 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine(340 mg, 1.561 mmol) using potassium carbonate (288 mg, 2.08 mmol) TBAB(50 mg, 0.156 mmol) and Pd(dppf)Cl₂ (54 mg, 0.078 mmol) in dioxane/water(10/3 mL) to get the crude product. The resultant crude was purified by60-120 silica gel column chromatography using 50% ethyl acetate inhexane as eluent to obtain the title compound (301 mg, 89%). LCMS: 100%,m/z=217.8 (M+1)⁺.

Step 2: Preparation of 5-(2-methylpyridin-4-yl)furan-2-carboxylic acid

Using the same reaction conditions as described in step 2 ofintermediate 5, methyl 5-(2-methylpyridin-4-yl)furan-2-carboxylate (300mg, 1.38 mmol) was hydrolysed using lithium hydroxide (116 mg, 2.76mmol) in THF/methanol/water (10/5/5 mL) at 50° C. for 0.25 h to obtainthe title compound (260 mg, 92.8%). LCMS: 100%, m/z=204.1 (M+1)⁺.

Intermediate 19: Synthesis of2-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)oxazole-4-carboxylic acid

Step 1: Preparation of ethyl2-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)oxazole-4-carboxylate

Using the same reaction conditions as described in step 7 of example 1,tert-butyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate(487 mg, 1.5223 mmol) was coupled with ethyl2-chlorooxazole-4-carboxylate (165 mg, 1.1710 mmol) using sodiumcarbonate (373 mg, 3.5131 mmol) and Pd(dppf)Cl₂ (43 mg, 0.0585 mmol) in1,2-dimethoxyethane/water (10/5 mL) to get the crude product. Theresultant crude was purified by 60-120 silica gel column chromatographyusing 30% ethyl acetate in hexane as eluent to obtain the title compound(200 mg, 43.9%). LCMS: m/z=278.0 (M+1-t-butyl)⁺.

Step 2: Preparation of2-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)oxazole-4-carboxylic acid

Using the same reaction conditions as described in step 2 ofintermediate 5, ethyl2-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)oxazole-4-carboxylate (145mg, 0.4349 mmol) was hydrolysed using 10% sodium hydroxide solution (1mL) in THF/methanol/water (10/5/2 mL) at RT for 10 min to obtain thetitle compound (75 mg, 56.81%). LCMS: m/z: 250.0 (M+1-de-t-butyl)⁺.

Intermediate 20: Synthesis of2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylic acid

Step 1: Preparation of ethyl2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylate

Using the same reaction conditions as described in step 7 of example 1,N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide(2.78 g, 10.04 mmol) was coupled with ethyl2-chlorooxazole-4-carboxylate (1 g, 7.09 mmol) using sodium carbonate(106 mg, 21.2 mmol) and Pd(dppf)Cl₂ (259 mg, 0.354 mmol) in1,2-dimethoxyethane/water (30/5 mL) to get the crude product. Theresultant crude was purified by 60-120 silica gel column chromatographyusing 50% ethyl acetate in hexane as eluent to obtain the title compound(680 mg, 36%). LCMS: m/z: 276.3 (M+1)⁺.

Step 2: Preparation of 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylicacid

Using the same reaction conditions as described in step 2 ofintermediate 5, ethyl 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylate(500 mg, 1.81 mmol) was hydrolysed using lithium hydroxide (84 mg, 2mmol) in THF/methanol/water (10/1/5 mL) at RT for 4 h to obtain thetitle compound (360 mg, 81.08%). LCMS: m/z: 248.1 (M+1)⁺.

Intermediate 21: Synthesis of2-(2-aminopyridin-4-yl)oxazole-4-carboxylic acid

Using the same reaction conditions as described in step 2 ofintermediate 5, ethyl 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylate(product of step 1 of intermediate 20) (900 mg, 3.27 mmol) washydrolysed using lithium hydroxide (329 mg, 7.85 mmol) inTHF/methanol/water (30/1/5 mL) at RT for 4 h to obtain the titlecompound (750 mg, 96%). LCMS: m/z: 206.2 (M+1)⁺.

Intermediate 22: Synthesis of5-(2-acetamidopyridin-4-yl)furan-2-carboxylic acid

Step 1: Preparation of methyl5-(2-acetamidopyridin-4-yl)furan-2-carboxylate

Using the same reaction conditions as described in step 7 of example 1,N-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)acetamide(1.91 g, 7.317 mmol) was coupled with methyl 5-bromofuran-2-carboxylate(1 g, 4.87 mmol) using sodium carbonate (1.54 g, 14.61 mmol) andPd(dppf)Cl₂ (178 mg, 0.243 mmol) in 1,2-dimethoxyethane/water (20/4 mL)at 80° C. for 3 h to get the crude product. The resultant crude waspurified by flash chromatography using 35% ethyl acetate in hexane aseluent to obtain the title compound (451 mg, 35.6%). LCMS: m/z: 261.1(M+1)⁺.

Step 2: Preparation of 5-(2-acetamidopyridin-4-yl)furan-2-carboxylicacid

Using the same reaction conditions as described in step 2 ofintermediate 5, ethyl 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylate(450 mg, 1.73 mmol) was hydrolysed using lithium hydroxide (73 mg, 1.73mmol) in THF/methanol/water (10/5/5 mL) at RT for 2 h to obtain thetitle compound (396 mg, 93.17%). LCMS: m/z: 247.2 (M+1)⁺.

Intermediate 23: Synthesis of2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

To a solution of 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid(WO2011/043371) (0.25 g, 1.22 mmol) in DMF were added ammonium chloride(0.131 g, 2.45 mmol), EDCI.HCl (0.351 g, 1.83 mmol), HOBT (0.248 g, 1.83mmol) and DIPEA (0.790 g, 6.12 mmol). The reaction mixture was stirredfor 12 h at room temperature and was diluted with EtOAc, washed withbrine and dried over Na₂SO₄ and concentrated to afford the titlecompound (0.180 g, 75%) as a white solid.

¹H NMR (300 MHz, CDCl₃): δ 8.65 (d, 1H), 7.81-7.79 (m, 2H), 7.72 (d,1H), 7.65 (s, 1H), 2.55 (s, 3H); MS (ES): m/z: 204 (M+1)+; HPLC: 93.5%

EXAMPLES Example 16′-amino-N-(2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamide

Step 1: Preparation of oxazolo[4,5-b]pyridine-2-thiol

A solution of 2-aminopyridin-3-ol (5.0 g, 45.45 mmol) and potassiumethyl xanthate (8.0 g, 49.99 mmol) in pyridine (50 mL) was heated at110° C. overnight. The reaction mixture was cooled to 0° C., added icewater and acidified with Conc. HCl. The solid was filtered and driedunder vacuum to afford the title compound (6.0 g, 86.95%).

¹HNMR (DMSO-d₆, 300 MHz): δ 8.24-8.22 (d, 1H), 7.90-7.87 (d, 1H),7.30-7.26 (m, 1H). LCMS: m/z: 153.0 (M+1)⁺.

Step 2: Preparation of 2-(methylthio)oxazolo[4,5-b]pyridine

To a stirred solution of oxazolo[4,5-b]pyridine-2-thiol (3.0 g, 19.73mmol) in ethyl acetate (30 mL) was added potassium carbonate (3.81 g,27.62 mmol) and methyl iodide (3.08 g, 21.71 mmol) and stirred at RTovernight. The reaction mixture was diluted with water (100 ml),extracted with ethyl acetate (2×50 mL), dried over sodium sulphate andconcentrated to afford the title compound (3.0 g, 93.75%).

¹HNMR (CDCl₃, 300 MHz): δ 8.46-8.44 (d, 1H), 7.71-7.68 (d, 1H),7.20-7.15 (m, 1H), 2.81 (s, 3H). LCMS: m/z: 167.0 (M+1)⁺.

Step 3: Preparation of 2-morpholinooxazolo[4,5-b]pyridine

To a solution of 2-(methylthio)oxazolo[4,5-b]pyridine (2.0 g, 12.12mmol) in THF (5 mL) was added morpholine (5 mL) and heated at 75° C.overnight. The solvent was distilled off to afford the title compound(2.0 g, 83.3%).

¹HNMR (DMSO-d₆, 300 MHz): δ 8.20-8.10 (d, 1H), 7.80-7.70 (d, 1H),7.15-7.00 (m, 1H), 3.75-3.72 (m, 4H), 3.63-3.52 (m, 4H). LCMS: m/z:206.5 (M+1)⁺.

Step 4: Preparation of 2-morpholino-6-nitrooxazolo[4,5-b]pyridine

To a solution of 2-morpholinooxazolo[4,5-b]pyridine (1.0 g, 4.854 mmol)in acetic acid (10 mL), was added fuming nitric acid (6 mL) and heatedat 100° C. for 4 hrs. The reaction mixture was cooled to 0° C., addedice and filtered the solid to afford the title compound (800 mg, 66.6%).

¹HNMR (DMSO-d₆, 300 MHz): δ 9.11-9.10 (d, 1H), 8.567-8.560 (d, 1H), 3.75(s, 8H). LCMS: m/z: 250.9 (M+1)⁺.

Step 5: Preparation of 2-morpholinooxazolo[4,5-b]pyridin-6-amine

To a solution of 2-morpholino-6-nitrooxazolo[4,5-b]pyridine (700 mg, 2.8mmol) in THF was added ammonium chloride (2.37 g, 44.80 mmol) in water(5 mL) and zinc dust (1.82 g, 28.0 mmol) and stirred at 50° C. for 1 hr.The catalyst was filtered through Celite®, extracted with DCM (2×100 mL)and distilled out the solvent to get the title compound (600 mg, 97.4%).LCMS: m/z: 221.1 (M+1)⁺.

Step 6: Preparation of6-bromo-N-(2-morpholinooxazolo[4,5-b]pyridin-6-yl)picolinamide

The solution of 2-morpholinooxazolo[4,5-b]pyridin-6-amine (600 mg, 2.727mmol), 6-bromopicolinic acid (661 mg, 3.27 mmol), EDCI.HCl (797 mg, 4.09mmol), HOBt (552 mg, 4.09 mmol), DIPEA (1.05 g, 8.181 mmol) in DMF (5mL) was stirred at RT overnight. Thr reaction mixture was quenched withice water and extracted the compound in ethyl acetate (2×25 mL), driedover sodium sulphate and concentrated. The resultant crude was filteredby using 60-120 silica-gel column chromatography and compound was elutedusing 5% methanol in DCM as eluent to afford the title compound (350 mg,31.8%).

¹HNMR (CDCl₃, 300 MHz): δ 9.79 (s, 1H), 8.46-8.45 (d, 1H), 8.32-8.31 (d,1H), 8.26-8.23 (d, 1H), 7.82-7.68 (m, 2H), 3.85-3.67 (m, 8H). LCMS: m/z:405.6 (M+1)⁺.

Step 7: Preparation of tert-butyl(6-((2-morpholinooxazolo[4,5-b]pyridin-6-yl)carbamoyl)-[2,3′-bipyridin]-6′-yl)carbamate

To a sealed tube6-bromo-N-(2-morpholinooxazolo[4,5-b]pyridin-6-yl)picolinamide (350 mg,0.866 mmol), tert-butyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate(360 mg, 1.126 mmol) (intermediate 1), sodium carbonate (275 mg, 2.598mmol) in 1,2-dimethoxyethane (10 mL) and water (2 mL) were added. Thereaction mixture was purged with argon for 10 min, added Pd(PPh₃)₂Cl₂(31 mg, 0.043 mmol) and heated at 95° C. overnight. The solvent wasdistilled out. The resultant crude was purified by 60-120 silica gelcolumn chromatography using 5% methanol in DCM as eluent to obtain thetitle compound (300 mg, 67.11%). LCMS: m/z: 517.7 (M+1)⁺.

Step 8:6′-amino-N-(2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamide

TFA (5 mL) was added to the solution of tert-butyl(6-((2-morpholinooxazolo[4,5-b]pyridin-6-yl)carbamoyl)-[2,3′-bipyridin]-6′-yl)carbamate(300 mg, 0.580 mmol) in DCM (1 mL) and stirred at RT for 1 hr. Aftercompletion of the reaction, this was then purified by prep. HPLC toobtain the title compound (34 mg, 14.05%).

¹HNMR (DMSO-d₆, 300 MHz): δ 10.06 (s, 1H), 8.96-8.95 (d, 1H), 8.58-8.44(d, 1H), 8.44-8.40 (dd, 1H), 8.31-8.30 (d, 1H), 8.11-7.95 (m, 3H),6.59-6.56 (d, 1H), 6.38 (s, 2H), 3.75-3.66 (m, 8H).

LCMS: 98.20%, m/z=418.1 (M+1)⁺. HPLC: 98.32%.

Example 26′-amino-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamidehydrochloride

Step 1: Preparation of 2-amino-6-chloropyridin-3-ol

Using the same reaction conditions as described in step 5 of example 1,6-chloro-2-nitropyridin-3-ol (35 mg, 0.201 mmol) was reduced with zincdust (65 mg, 1.005 mmol) and ammonium chloride (54 mg, 1.005 mmol) inTHF (2 mL) to get the title compound (25 mg, 89%).

LCMS: m/z: 145.2 (M+1)⁺.

Step 2: Preparation of 5-chlorooxazolo[4,5-b]pyridine-2-thiol

Using the same reaction conditions as described in step 1 of example 12-amino-6-chloropyridin-3-ol (25 mg, 0.173 mmol) was cyclised usingpotassium ethyl xanthate (33 mg, 0.208 mmol) in pyridine (1 mL) toafford the title compound (25 mg, 78%).

¹HNMR (DMSO-d₆, 300 MHz): δ 7.94-7.90 (d, 1H), 7.38-7.35 (d, 1H). LCMS:m/z: 187.1 (M+1)⁺.

Step 3: Preparation of 5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 2 of example 1,5-chlorooxazolo[4,5-b]pyridine-2-thiol (620 mg, 3.33 mmol) wasmethylated using potassium carbonate (689 mg, 4.99 mmol) and methyliodide (567 mg, 3.99 mmol) in ethyl acetate (10 mL) to afford the titlecompound (720 mg, 90%). LCMS: m/z: 201.1 (M+1)⁺.

Step 4: Preparation of 5-chloro-2-morpholinooxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 3 of example 1,5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine was substituted usingmorpholine (2 mL) and THF (10 mL) to afford the title compound (750 mg,88%).

¹HNMR (DMSO-d₆, 400 MHz): δ 7.82-7.80 (d, 1H), 7.08-7.06 (d, 1H),3.74-3.64 (m, 8H). LCMS: m/z: 240.2 (M+1)⁺.

Step 5: Preparation of5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 4 of example 15-chloro-2-morpholinooxazolo[4,5-b]pyridine (50 mg) was nitrated usingacetic acid (0.2 mL) and fuming nitric acid (0.1 mL) at 100° C. for 2 hto afford the title compound (25 mg, 43%).

¹HNMR (DMSO-d₆, 300 MHz): δ 8.60 (s, 1H), 3.72 (s, 8H)⁺.

Step 6: Preparation of5-cyclopropyl-2-morpholino-6-nitrooxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 7 of example 15-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (25 mg, 0.088 mmol)was coupled with cyclopropyl boronic acid (9 mg, 0.105 mmol) usingpotassium carbonate (24 mg, 0.176 mmol) and Pd(PPh₃)₄ (5 mg, 0.004 mmol)in xylene (2 mL) to get the crude product (50 mg). LCMS: m/z: 291.1(M+1)⁺.

Step 7: Preparation of5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,5-cyclopropyl-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (220 mg, 0.758mmol) was reduced with zinc dust (394 mg, 6.068 mmol) and ammoniumchloride (327 mg, 6.068 mmol) in THF/methanol/H₂O (5 mL/1 ml/0.5 mL) toget the title compound (160 mg, 84%). LCMS: m/z: 261.0 (M+1)⁺.

Step 8: Preparation of6-bromo-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)picolinamide

Using the same reaction conditions as described in step 6 of example 1,5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-amine (100 mg, 0.384mmol), was coupled with 6-bromopicolinic acid (85 mg, 0.423 mmol) usingEDCI.HCl (110 mg, 0.576 mmol), HOBt (77 mg, 0.576 mmol), TEA (0.22 mL,1.538 mmol) in DMF (2 mL) to afford the title compound (75 mg, 44%).LCMS: m/z: 444.2 (M+1)⁺.

Step 9: Preparation of tert-butyl(6-((5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)carbamoyl)-[2,3′-bipyridin]-6′-yl)carbamate

Using the same reaction conditions as described in step 7 of example 1,6-bromo-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)picolinamide(75 mg, 0.169 mmol) was coupled with tert-butyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate(65 mg, 0.203 mmol) (intermediate 1) using sodium carbonate (53 mg,0.507 mmol) and Pd(PPh₃)₂Cl₂ (7 mg, 0.0084 mmol) in 1,2-dimethoxyethane(5 mL) to get the crude product. The resultant crude was purified by60-120 silica gel column chromatography using 50% ethyl acetate inhexane as eluent to obtain the title compound (50 mg, 54%). LCMS: m/z:558.2 (M+1)⁺.

Step 10: Preparation of6′-amino-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamide

Using the same reaction conditions as described in step 8 of example 1tert-butyl(6-((5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)carbamoyl)-[2,3′-bipyridin]-6′-yl)carbamate(50 mg, 0.089 mmol) was deprotected using methanolic HCl (5 mL) to getthe crude product. This was then purified by prep HPLC to get the titlecompound (40 mg, 90%).

¹HNMR (DMSO-d₆, 400 MHz): δ 10.78 (s, 1H), 9.059-9.055 (d, 1H),8.93-8.90 (dd, 1H), 8.40-8.25 (bs, 2H), 8.21-8.20 (d, 1H), 8.15-8.11 (t,1H), 8.07-8.05 (d, 1H), 7.83 (s, 1H), 7.12-7.09 (d, 1H), 3.71-3.60 (m,8H), 2.20-2.16 (m, 1H), 0.91-0.87 (m, 4H).

LCMS: 96.48%, m/z=458.2 (M+1)⁺. HPLC: 98.7%.

Example 3N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride

Using the same reaction conditions as described in step 6 of example 1,5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-amine (product of step7 of example 2) (60 mg, 0.23 mmol), was coupled with2-(2-methyl-pyridin-4-yl)oxazole-4-carboxylic acid (71 mg, 0.396 mmol)using EDCI.HCl (66 mg, 0.396 mmol), HOBt (46 mg, 0.396 mmol), TEA (0.13mL, 0.923 mmol) in DMF (2 mL) to afford the crude product. This was thenpurified by prep HPLC and treated with methanolic HCl to get the titlecompound (20 mg, 20%).

¹HNMR (DMSO-d₆, 400 MHz): δ 10.22 (s, 1H), 9.27 (s, 1H), 8.85-8.83 (d,1H), 8.25 (s, 1H), 8.14-8.13 (d, 1H), 7.72 (s, 1H), 3.71-3.59 (m, 8H),2.63 (s, 3H), 2.17-2.14 (m, 1H), 0.89-0.86 (m, 4H).

LCMS: 93.91%, m/z=447.1 (M+1)⁺. HPLC: 99.0%.

Example 4:N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamidehydrochloride

Step 1: Preparation of 5-chloro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 3 of example 1,5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (product of step 3 ofexample 2) (3 g, 14.95 mmol) was substituted using piperidine (8 mL) andTHF (30 mL) to afford the title compound (3 g, 90%).

LCMS: m/z=238.1 (M+1)⁺.

Step 2: Preparation of5-chloro-6-nitro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 4 of example 20,5-chloro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine (4 g, 168 mmol) wasnitrated using potassium nitrate (3.4 g, 337 mmol) and conc. sulphuricacid (20 mL) at RT for 3 h to afford the crude title compound (4g).

LCMS: m/z=283.0 (M+1)⁺.

Step 3: Preparation of6-nitro-2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridine

A mixture of 5-chloro-6-nitro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine(product of step 5 of example 2) (300 mg, 1.056 mmol) was heated withpiperidine (3 mL) at 100° C. for 2 h. Reaction was quenched with icewater and filtered the solid to get the title compound (300 mg, 86%).

LCMS: m/z: 332.1 (M+1)⁺.

Step 4: Preparation of2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,6-nitro-2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridine (300 mg, 0.90 mmol)was reduced with zinc dust (468 mg, 7.207 mmol) and ammonium chloride(389 mg, 7.207 mmol) in THF/methanol/H₂O (5 mL/1 mL/0.5 mL) to get thetitle compound (250 mg, 92%). LCMS: m/z: 302.4 (M+1)⁺.

Step 5: Preparation ofN-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide

Using the same reaction conditions as described in step 6 of example 1,2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (100 mg, 0.33 mmol),was coupled with6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid(intermediate 3) (108 mg, 0.396 mmol) using EDCI.HCl (94 mg, 0.495mmol), HOBt (66 mg, 0.495 mmol), TEA (0.2 mL, 1.324 mmol) in DMF (2 mL)to afford the crude product. The resultant crude was purified by 60-120silica gel column chromatography using 1% methanol in DCM as eluent toobtain the title compound (100 mg, 55%).

LCMS: m/z: 557.4 (M+1)⁺.

Step 6: Preparation ofN-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamidehydrochloride

Using the same reaction conditions as described in step 8 of example 1,N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide(100 mg, 0.179 mmol) was deprotected using methanolic HCl to get thecrude product. This was then purified by prep HPLC to get the titlecompound (40 mg, 50%).

¹HNMR (DMSO-d₆, 300 MHz): δ 10.8 (s, 1H), 8.66 (s, 1H), 8.39 (s, 1H),8.04-7.94 (m, 3H), 3.62 (s, 4H), 2.94 (s, 4H), 1.75 (s, 4H), 1.62-1.55(m, 8H).

LCMS: 97.91%, m/z=473.5 (M+1)⁺. HPLC: 96.5%.

Example 5N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of step 4of example 4) (100 mg, 0.33 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (74 mg, 0.363 mmol)using EDCI.HCl (94 mg, 0.495 mmol), HOBt (66 mg, 0.495 mmol), TEA (0.2mL, 1.324 mmol) in DMF (2 mL) to afford the crude product. This was thenpurified by prep HPLC to get the title compound (30 mg, 20%).

¹HNMR (DMSO-d₆, 300 MHz): δ 9.98 (s, 1H), 9.21 (s, 1H), 8.91-8.89 (d,1H), 8.51 (s, 1H), 8.21 (s, 1H), 8.09-8.08 (d, 1H), 3.61 (m, 7H), 2.98(s, 3H), 2.71 (s, 3H), 1.81 (s, 3H), 1.61 (s, 7H). LCMS: 100%, m/z=488.2(M+1)⁺. HPLC: 92.1%.

Example 6N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide

Step 1: Preparation of2-morpholino-6-nitro-5-(piperidin-1-yl)oxazolo[4,5-b]pyridine

To a solution of 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine(product of step-5 of example 2) (30 mg, 0.1056 mmol) in THF (2 mL) wasadded piperidine (11 mg, 0.126 mmol) and stirred at RT overnight. Thereaction mixture was quenched with ice water and extracted with ethylacetate (2×10 mL), dried over sodium sulphate and distilled out thesolvent to obtain the title compound (30 mg, 89%). LCMS: m/z: 334.5(M+1)⁺.

Step 2: Preparation of2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,2-morpholino-6-nitro-5-(piperidin-1-yl)oxazolo[4,5-b]pyridine (300 mg,0.900 mmol) was reduced with zinc dust (468 mg, 7.207 mmol) and ammoniumchloride (389 mg, 7.207 mmol) in THF/methanol/H₂O (5 mL/1 mL/0.5 mL) toget the title compound (260 mg, 96%). LCMS: m/z: 304.1 (M+1)⁺.

Step 3: Preparation ofN-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (90 mg,0.297 mmol), was coupled with6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid(intermediate 3) (97 mg, 0.356 mmol) using EDCI.HCl (85 mg, 0.445 mmol),HOBt (60 mg, 0.445 mmol), TEA (0.2 mL, 1.188 mmol) in DMF (4 mL) toafford the crude product. The resultant crude was purified by 60-120silica gel column chromatography using 1% methanol in DCM as eluent toobtain the title compound (60 mg, 38%). LCMS: m/z: 559.6 (M+1)⁺.

Step 4: Preparation ofN-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide

Using the same reaction conditions as described in step 8 of example 1,N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide(60 mg, 0.107 mmol) was deprotected using methanolic HCl (2 mL) to getthe title compound (50 mg, 90%).

¹HNMR (DMSO-d₆, 300 MHz): δ 10.80 (s, 1H), 8.65 (s, 1H), 8.43 (s, 2H),8.05-7.93 (m, 3H), 3.76-3.62 (m, 8H), 2.98 (s, 4H), 1.76 (s, 4H), 1.54(s, 2H). LCMS: 92.69%, m/z=475.5 (M+1)⁺.

HPLC: 90.31%.

Example 72-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product ofstep 2 of example 6) (100 mg, 0.331 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (81 mg, 0.397 mmol)using EDCI.HCl (94 mg, 0.496 mmol), HOBt (66 mg, 0.496 mmol), TEA (0.2mL, 1.302 mmol) in DMF (2 mL) to afford the crude product. The resultantcrude was purified by 60-120 silica gel column chromatography using 1%methanol in DCM as eluent to obtain the title compound (35 mg, 22%).

¹HNMR (DMSO-d₆, 300 MHz): δ 9.80 (s, 1H), 9.20 (s, 1H), 8.90-8.88 (d,1H), 8.57 (s, 1H), 8.18 (s, 1H), 8.06-8.04 (d, 1H), 3.72-3.61 (m, 8H),2.96 (s, 4H), 2.73 (s, 3H), 1.81 (s, 4H), 1.63 (s, 2H).

LCMS: 81.6%, m/z=490.2 (M+1)⁺. HPLC: 94.3%.

Example 86-chloro-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product ofstep 2 of example 6) (70 mg, 0.2317 mmol), was coupled with6-chloropicolinic acid (44 mg, 0.278 mmol) using EDCI.HCl (66 mg, 0.347mmol), HOBt (46 mg, 0.347 mmol), TEA (0.2 mL, 0.926 mmol) in DMF (4 mL)to afford the crude product. The resultant crude was purified by 60-120silica gel column chromatography using 1% methanol in DCM as eluent toobtain the title compound (35 mg, 35%).

¹HNMR (DMSO-d₆, 300 MHz): δ 10.60 (s, 1H), 8.70 (s, 1H), 8.15-8.14 (t,2H), 7.84-7.81 (m, 1H), 3.77-3.60 (m, 8H), 2.93-2.10 (t, 4H), 1.81 (s,4H), 1.58 (s, 2H). LCMS: 99.3%, m/z=443.2 (M+1)⁺. HPLC: 93.0%.

Example 9N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide

Using the same reaction conditions as described in step 6 of example 1,2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of step 2of example 4) (75 mg, 0.2483 mmol), was coupled with6-(1-methyl-1H-pyrazol-4-yl)picolinic acid (intermediate 4)(61 mg, 0.298mmol) using EDCI.HCl (72 mg, 0.372 mmol), HOBt (51 mg, 0.372 mmol),DIPEA (0.17 mL, 0.9933 mmol) in DMF (2 mL) to afford the crude product.This was then purified by prep HPLC to get the title compound (41 mg,33.0%).

¹HNMR (DMSO-d₆, 400 MHz): δ 10.80 (s, 1H), 8.67 (s, 1H), 8.44 (s, 1H),8.21 (s, 1H), 8.06-8.02 (t, 1H), 7.98-7.96 (d, 1H), 7.92-7.91 (d, 1H),3.92 (s, 3H), 3.63 (s, 4H), 2.94 (s, 4H), 1.76 (s, 4H), 1.63 (s, 6H),1.55 (s, 2H). LCMS: 98.9%, m/z=487.2 (M+1)⁺. HPLC: 94.0%.

Example 102-(2-chloropyridin-4-yl)-N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of step 2of example 4) (75 mg, 0.2483 mmol), was coupled with2-(2-chloropyridin-4-yl)oxazole-4-carboxylic acid (71 mg, 0.298 mmol)using EDCI.HCl (72 mg, 0.372 mmol), HOBt (51 mg, 0.372 mmol), DIPEA(0.17 mL, 0.9933 mmol) in DMF (2 mL) to afford the crude product. Thiswas then purified by prep HPLC to get the title compound (62 mg, 45.9%).

¹HNMR (CD₃OD, 400 MHz): δ 8.82 (s, 1H), 8.64-8.62 (d, 1H), 8.14 (s, 1H),8.04-8.03 (d, 1H), 3.81 (s, 8H), 2.06-1.96 (m, 4H), 1.79 (s, 8H). LCMS:84.1%, m/z=508.2 (M+1)⁺. HPLC: 97.6%.

Example 11(S)-2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-3-ylamino)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Step 1: Preparation of (S)-tert-butyl3-((2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine-1-carboxylate

A solution of 5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (300mg, 1.0563 mmol) (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (237mg, 1.267 mmol) and potassium carbonate (292 mg, 2.112 mmol) in DMF (2mL) was heated at 100° C. for 2 h. Reaction was quenched with ice waterand filtered the solid. The resultant crude was purified by 60-120silica gel column chromatography using 1% methanol in DCM as eluent toobtain the title compound (350 mg, 76.25%). LCMS: m/z: 435.4 (M+1)⁺.

Step 2: Preparation of (S)-tert-butyl3-((6-amino-2-morpholinooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine-1-carboxylate

Using the same reaction conditions as described in step 5 of example 1,(S)-tert-butyl3-((2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine-1-carboxylate(350 mg, 0.806 mmol) was reduced with zinc dust (422 mg, 6.451 mmol) andammonium chloride (691 mg, 12.903 mmol) in THF/methanol/H₂O (10 mL/2mL/1 mL) to get the title compound (240 mg, 71.8%). LCMS: m/z: 405.2(M+1)⁺.

Step 3: Preparation of (S)-tert-butyl3-((6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine-1-carboxylate

Using the same reaction conditions as described in step 6 of example 1,(S)-tert-butyl3-((6-amino-2-morpholinooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine-1-carboxylate(115 mg, 0.284 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (70 mg, 0.341 mmol)using EDCI.HCl (82 mg, 0.426 mmol), HOBt (58 mg, 0.426 mmol), DIPEA(0.199 mL, 1.138 mmol) in DMF (2 mL) to afford the title compound (100mg, 59.52%). LCMS: m/z: 591.4 (M+1)⁺.

Step 4: Preparation of(S)-2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-3-ylamino)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 8 of example 1,(S)-tert-butyl3-((6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinooxazolo[4,5-b]pyridin-5-yl)amino)pyrrolidine-1-carboxylate(100 mg, 0.169 mmol) was deprotected using methanolic HCl (5 mL) to getthe crude product. This was then purified by prep HPLC to get the titlecompound (9 mg, 10.84%).

¹HNMR (CDCl₃, 400 MHz): δ 9.91 (s, 1H), 8.78 (s, 1H), 8.74-8.73 (d, 1H),8.45 (s, 1H), 7.82 (s, 1H), 7.76-7.74 (d, 1H), 4.50 (s, 1H), 4.04-4.03(d, 4H), 3.30-3.00 (m, 7H), 2.70 (s, 3H), 2.40-1.80 (m, 4H), 1.00-0.08(m, 1H). LCMS: 100%, m/z=491.3 (M+1)⁺.

Example 126′-amino-N-(2-morpholinooxazolo[5,4-b]pyridin-5-yl)-[2,3′-bipyridine]-6-carboxamide

Step 1: Preparation of 3-amino-6-chloropyridin-2-ol

Using the same reaction conditions as described in step 5 of example 16-chloro-3-nitropyridin-2-ol (1.0 g, 5.747 mmol was reduced with zincdust (3.0 g, 45.977 mmol) and ammonium chloride (4.92 g, 91.952 mmol) inTHF/methanol/H₂O (20 m/4 mL/2 mL) to get the crude product. Theresultant crude was purified by 60-120 silica gel column chromatographyusing 10% methanol in DCM as eluent to obtain the title compound (500mg, 60.97%).

¹HNMR (DMSO-d₆, 300 MHz): δ 6.84-6.81 (d, 1H), 6.55-6.52 (d, 1H). LCMS:m/z: 145.0 (M+1)⁺.

Step 2: Preparation of 5-chlorooxazolo[5,4-b]pyridine-2-thiol

Using the same reaction conditions as described in step 1 of example 1,3-amino-6-chloropyridin-2-ol (900 mg, 6.25 mmol) was cyclised usingpotassium ethyl xanthate (1.1 g, 6.875 mmol) in pyridine (8 mL) toafford the title compound (1.0 g, 86.2%). LCMS: m/z: 185.0 (M−1)⁺.

Step 3: Preparation of 5-chloro-2-morpholinooxazolo[5,4-b]pyridine

The mixture of 5-chlorooxazolo[5,4-b]pyridine-2-thiol (550 mg, 2.956mmol), morpholine (5 mL) and heated at 110° C. overnight. Solvent wasdistilled off. The resultant crude was purified by 60-120 silica gelcolumn chromatography using 40% ethyl acetate in hexane as eluent toobtain the title compound (200 mg, 28.5%). LCMS: m/z: 240.0 (M+1)⁺.

Step 4: Preparation of6′-amino-N-(2-morpholinooxazolo[5,4-b]pyridin-5-yl)-[2,3′-bipyridine]-6-carboxamide

In a sealed tube, taken 5-chloro-2-morpholinooxazolo[5,4-b]pyridine (76mg, 0.316 mmol), tert-butyl(6-carbamoyl-[2,3′-bipyridin]-6′-yl)carbamate (100 mg, 0.316 mmol)(intermediate 2) and caesium carbonate (257 mg, 0.79 mmol) in toluene (5mL) and purged argon for 10 min. Added X-Phos (15 mg, 0.32 mmol) andheated at 110° C. overnight. The solvent was distilled out. Theresultant crude was purified by 60-120 silica gel column chromatographyusing 5% methanol in DCM as eluent. Further The resultant crude waspurified by prep HPLC to obtain the title compound (11 mg, 10.0%).

¹HNMR (CDCl₃, 300 MHz): δ 8.81 (s, 1H), 8.25-8.24 (d, 1H), 8.10 (s, 1H),7.80-7.75 (m, 3H), 7.50-7.44 (m, 1H), 7.25 (s, 1H), 3.77-3.62 (m, 8H).LCMS: 72.3%, m/z=418.2 (M+1)⁺. HPLC: 96.1%.

Example 136′-amino-N-(2-morpholinothiazolo[4,5-c]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamide

Step-1: Synthesis of 6-chloro thiazolo[4,5-c]pyridine-2(3H)-thione

Using the same reaction conditions as described in step 1 of example 1,4,6-dichloropyridin-3-amine (1.3 g, 7 mmol) was cyclised using potassiumethyl xanthate (2.55 g, 15 mmol) in DMF (25 mL) at 150° C. for 8 h toafford the title compound (1.3 g, 86.6%) as a light brown solid.

¹HNMR (400 MHz, DMSO-d₆): δ 14.2-14.0 (b, 1H), 8.274 (s, 1H), 7.931 (s,1H); LCMS: 100%, m/z=201.3 (M+1)⁺.

Step-2: Synthesis of 4-(6-chloro thiazolo[4,5-c]pyridin-2-yl) morpholine

To a suspension of 6-chlorothiazolo[4,5-c]pyridine-2(3H)-thione (0.3 g,1.16 mmol) in DCM (4 mL), oxalyl chloride (0.2 mL, 2.38 mmol) and DMF(1.5 mL) were added at 0° C. The resulting mixture was slowly allowed towarm to room temperature and stirred there for 1 h. The reaction mixturewas again cooled to 0° C. and triethyl amine (0.66 mL, 4.76 mmol) andmorpholine (0.13 mL, 1.75 mmol) were added. The reaction mixture wasstirred at RT for 1 h and quenched with water and extracted with ethylacetate. The combined organic layers were washed with water, brine,dried over sodium sulphate and concentrated under reduced pressure. Thecrude material was purified by column chromatography (EtOAc/n-hexanes3:7) to afford the title compound (0.14 g, 39.6%) as a light brownsolid.

¹H NMR (400 MHz, DMSO-d₆): δ 8.47 (s, 1H), 8.04 (s, 1H), 3.74-3.72 (m,4H), 3.61-3.59 (m, 4H); LCMS: m/z=256.1 (M+1)⁺.

Step-3: Synthesis of 6′-amino-N-(2-morpholino thiazolo[4,5-c]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamide

Using the same reaction conditions as described in step 4 of example 12,4-(6-chlorothiazolo[4,5-c]pyridin-2-yl) morpholine (0.081 g, 0.32 mmol),was coupled with tert-butyl(6-carbamoyl-[2,3′-bipyridin]-6′-yl)carbamate (intermediate 2) (0.1 g,0.32 mmol) using cesium carbonate (0.21 g, 0.64 mmol), XantPhos (0.028g, 0.047 mmol) and Pd₂(dba)₃ (0.015 mg, 0.015 mmol) in toluene:dioxane(2:2 mL) to get the crude product. The resultant crude was purified by60-120 silica gel column chromatography using 2% methanol in DCM aseluent. Further the resultant crude was purified by prep HPLC to affordtitle compound (0.01 g, 6%) as an off-white solid.

¹H NMR (400 MHz, DMSO-d₆): δ 10.65 (s, 1H), 8.88 (d, 1H), 8.85 (dd, 1H),8.71 (s, 1H), 8.55 (s, 1H), 8.22-8.13 (m, 4H), 7.09 (d, 1H), 3.73 (t,4H), 3.58 (t, 4H). LCMS: 100%, m/z=434.2 (M+1)⁺.

Example 146′-amino-N-(2-morpholinothiazolo[5,4-b]pyridin-5-yl)-[2,3′-bipyridine]-6-carboxamide

Step 1: Preparation of 5-chlorothiazolo[5,4-b]pyridine-2-thiol

Using the same reaction conditions as described in step 1 of example 1,2,6-dichloropyridin-3-amine (5 g, 30 mmol) was cyclised using potassiumethyl xanthate (9.81 g, 61 mmol) in NMP (40 mL) at 150° C. for overnightto afford the title compound (5.5 gr, 92%). 1HNMR (DMSO-d₆, 300 MHz): δ14.10 (bs, 1H), 7.66-7.62 (d, 1H), 7.53-7.48 (d, 1H). LCMS: m/z: 202.9(M+1)⁺.

Step 2: Preparation of 4-(5-chlorothiazolo[5,4-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 1 of example 4,5-chlorothiazolo[5,4-b]pyridine-2-thiol (5.5 g, 27.22 mmol) wassubstituted using morpholine (40 mL) to afford the title compound (4 gr,58%).

¹HNMR (DMSO-d₆, 300 MHz): δ 7.83-7.80 (d, 1H), 7.42-7.39 (d, 1H),3.75-3.71 (m, 4H), 3.61-3.58 (m, 4H). LCMS: m/z: 256.0 (M+1)⁺.

Step 3: Preparation of6′-amino-N-(2-morpholinothiazolo[5,4-b]pyridin-5-yl)-[2,3′-bipyridine]-6-carboxamide

Using the same reaction conditions as described in step 4 of example 12,6′-amino-N-(2-morpholinothiazolo[5,4-b]pyridin-5-yl)-[2,3′-bipyridine]-6-carboxamide(200 mg, 0.632 mmol), was coupled with tert-butyl(6-carbamoyl-[2,3′-bipyridin]-6′-yl)carbamate (intermediate 2) (177 mg,0.692 mmol) using cesium carbonate (514 mg, 1.582 mmol), X-Phos (30 mg,0.063 mmol) and Pd₂(dba)₃ (28 mg, 0.031 mmol) in toluene (5 mL) to getthe crude product. The resultant crude was purified by 60-120 silica gelcolumn chromatography using 2% methanol in DCM as eluent. Further Theresultant crude was purified by prep HPLC to obtain the title compound(13 mg, 5%).

¹HNMR (DMSO-d₆, 300 MHz): δ 10.06 (s, 1H), 9.17-9.16 (d, 1H), 8.64-8.60(m, 1H), 8.39 (s, 1H), 8.15-8.13 (d, 1H), 8.04-7.99 (t, 1H), 7.93-7.91(d, 1H), 7.80-7.69 (m, 4H), 3.75-3.72 (t, 4H), 3.55-3.52 (t, 4H). LCMS:96.5%, m/z=434.4 (M+1)⁺. HPLC: 95.1%.

Example 152-(2-methylpyridin-4-yl)-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Step 1: Preparation of thiazolo[4,5-b]pyridine-2-thiol

Using the same reaction conditions as described in step 1 of example 1,3-bromopyridin-2-amine (5 gr, 28 mmol) was cyclised using potassiumethyl xanthate (9.24 gr, 57 mmol) in NMP (40 mL) at 150° C. forovernight to afford the title compound (4.2 gr, 88%).

¹HNMR (DMSO-d₆, 300 MHz): δ 8.37-8.35 (m, 1H), 8.15-8.12 (m, 1H),7.32-7.28 (q, 1H) LCMS: m/z: 169.1 (M+1)⁺.

Step 2: Preparation of 4-(thiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 1 of example 4,thiazolo[4,5-b]pyridine-2-thiol (4.2 gr, 25 mmol) was substituted usingmorpholine (20 mL) at 110° C. to afford the title compound (3g, 55%).

¹HNMR (DMSO-d₆, 300 MHz): δ 8.32-8.30 (dd, 1H), 8.22-8.18 (dd, 1H),7.07-7.03 (q, 1H), 3.76-3.72 (m, 4H), 3.62-3.59 (m, 4H). LCMS: m/z:222.3 (M+1)⁺.

Step 3: Preparation of 4-(6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 4 of example 14-(thiazolo[4,5-b]pyridin-2-yl)morpholine (2.5 g, 11.3 mmol) wasnitrated using acetic acid (5 mL) and fuming nitric acid (10 mL) at 100°C. for overnight to afford the title compound (1.5 g, 50%). ¹HNMR(DMSO-d₆, 300 MHz): δ 9.15-9.09 (m, 2H), 3.70-3.60 (bs, 8H).

Step 4: Preparation of 2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 14-(6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (500 mg, 1.879 mmol)was reduced with zinc dust (977 mg, 15.03 mmol) and ammonium chloride(812 mg, 15.03 mmol) in THF/methanol/H₂O (10 mL/2 mL/1 mL) to get thetitle compound (430 mg, 97%).

¹HNMR (DMSO-d₆, 300 MHz): δ 7.75-7.74 (d, 1H), 7.36-7.35 (d, 1H),5.10-5.05 (bs, 2H), 3.73-3.70 (m, 4H), 3.48-3.34 (m, 4H). LCMS: m/z:237.4 (M+1)⁺.

Step 5: Preparation of2-(2-methylpyridin-4-yl)-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholinothiazolo[4,5-b]pyridin-6-amine (110 mg, 0.466 mmol), wascoupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (95 mg,0.466 mmol) using EDCI.HCl (133 mg, 0.699 mmol), HOBt (94 mg, 0.69mmol), DIPEA (0.2 mL, 1.165 mmol) in DMF (2 mL) to afford the crudeproduct. The resultant crude was purified by 60-120 silica gel columnchromatography using 2% methanol in DCM as eluent. The crude was furtherpurified by prep HPLC to obtain the title compound (28 mg, 15%).

¹HNMR (DMSO-d₆, 300 MHz): δ 10.45 (s, 1H), 9.01 (s, 1H), 8.70-8.63 (d,1H), 8.65-8.62 (dd, 2H), 7.89 (s, 1H), 7.80-7.75 (d, 1H), 3.77-3.72 (t,4H), 3.62-3.60 (t, 4H), 2.60 (s, 3H).

LCMS: 100%, m/z=423.2 (M+1)⁺. HPLC: 96.9%.

Example 166′-amino-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamide

Step 1: Preparation of6-bromo-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)picolinamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of step 4 of example15) (320 mg, 1.35 mmol), was coupled with 6-bromopicolinic acid (356 mg,1.76 mmol) using EDCI.HCl (698 mg, 5.4 mmol), HOBt (239 mg, 1.76 mmol),DIPEA (338 mL, 1.76 mmol) in DMF (5 mL) to afford the title compound(250 mg, 43.9%). LCMS: m/z: 421.6 (M+1)⁺.

Step 2: Preparation of tert-butyl(6-((2-morpholinothiazolo[4,5-b]pyridin-6-yl)carbamoyl)-[2,3′-bipyridin]-6′-yl)carbamate

Using the same reaction conditions as described in step 7 of example 16-bromo-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)picolinamide (250 mg,0.59 mmol) was coupled with tert-butyl(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)carbamate(151 mg, 0.71 mmol) (intermediate 1) using sodium carbonate (188 mg,1.77 mmol) and Pd(PPh₃)₂Cl₂ (22 mg, 0.029 mmol) in 1,2-dimethoxyethane(8 mL) to get the crude product. The resultant crude was purified byCombiflash using 0.2-2.0% methanol in chloroform as eluent to obtain thetitle compound (120 mg, 37.8%). LCMS: m/z: 534.2 (M+1)⁺.

Step 3: Preparation of6′-amino-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamide

Using the same reaction conditions as described in step 8 of example 1,tert-butyl(6-((2-morpholinothiazolo[4,5-b]pyridin-6-yl)carbamoyl)-[2,3′-bipyridin]-6′-yl)carbamate(120 mg, 0.22 mmol) was deprotected using TFA (12 mL) to get the titlecompound (80 mg, 82%).

¹HNMR (DMSO-d₆, 300 MHz): δ 10.65 (s, 1H), 8.96 (s, 1H), 8.71 (s, 1H),8.45-8.42 (d, 1H), 8.08-7.95 (m, 3H), 6.59-6.56 (d, 1H), 6.38 (s, 2H),3.76-3.74 (t, 4H), 3.63-3.62 (t, 4H). LCMS: 98.9%, m/z=434.1 (M+1)⁺.HPLC: 95.9%.

Example 17N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide

Using the same reaction conditions as described in step 7 of example 1,6-bromo-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)picolinamide (productof step 1 of example 16) (200 mg, 0.477 mmol) was coupled with4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (111 mg,0.572 mmol) using sodium carbonate (151 mg, 1.431 mmol) and Pd(PPh₃)₂Cl₂(35 mg, 0.0477 mmol) in 1,2-dimethoxyethane (5 mL) to get the crudeproduct. The resultant crude was purified by 60-120 silica gel columnchromatography using 2% methanol in DCM as eluent. Further it waspurified by prep HPLC to obtain the title compound (14 mg, 8%).

¹HNMR (DMSO-d₆, 400 MHz): δ 13.2 (s, 1H), 10.60 (s, 1H), 8.70-8.60 (m,3H), 8.40 (s, 1H), 8.02-7.91 (m, 3H), 3.76-3.74 (t, 4H), 3.62-3.60 (t,4H). LCMS: 100%, m/z=408.1 (M+1)⁺.

HPLC: 97.9%.

Example 183-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)benzamide

Step 1: tert-butyl((1-(3-fluoro-5-((2-morpholinothiazolo[4,5-b]pyridin-6-yl)carbamoyl)phenyl)piperidin-4-yl)methyl)carbamate

Using the same reaction conditions as described in step 6 of example 1,2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of step 4 of example15) (60 mg, 0.254 mmol), was coupled with3-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoicacid (intermediate 5) (98 mg, 0.279 mmol) using EDCI.HCl (72 mg, 0.381mmol), HOBt (52 mg, 0.381 mmol), DIPEA (98 mg, 0.762 mmol) in DMF (5 mL)to afford the title compound (130 mg, 90.2%).

LCMS: m/z: 571.2 (M+1)⁺.

Step2:3-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)benzamide

Using the same reaction conditions as described in step 8 of example 1,tert-butyl((1-(3-fluoro-5-((2-morpholinothiazolo[4,5-b]pyridin-6-yl)carbamoyl)phenyl)piperidin-4-yl)methyl)carbamate(130 mg, 0.228 mmol) was deprotected using methanolic HCl (4.7 mL) toget the crude compound. The resultant crude was purified by prep HPLC toobtain the title compound (55 mg, 47.8%).

¹HNMR (DMSO-d₆, 300 MHz): δ 10.74 (s, 1H), 8.87 (s, 1H), 8.69 (s, 1H),7.96 (s, 3H), 7.41 (s, 1H), 7.14-7.01 (m, 2H), 3.69-3.68 (m, 6H),2.83-2.73 (m, 5H), 2.27 (s, 1H), 1.85-1.81 (m, 4H), 1.30-1.23 (m, 3H).LCMS: 100%, m/z=471.5 (M+1)⁺. HPLC: 97.9%.

Example 192-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)benzamide

Step 1: Preparation of tert-butyl((1-(4-fluoro-2-((2-morpholinothiazolo[4,5-b]pyridin-6-yl)carbamoyl)phenyl)piperidin-4-yl)methyl)carbamate

Using the same reaction conditions as described in step 6 of example 1,2-morpholinothiazolo[4,5-b]pyridin-6-amine (product of step 4 of example15) (100 mg, 0.423 mmol), was coupled with2-(4-(((tert-butoxycarbonyl)amino)methyl)piperidin-1-yl)-5-fluorobenzoicacid (intermediate 6) (164 mg, 0.466 mmol) using EDCI.HCl (121 mg, 0.65mmol), HOBt (85 mg, 0.635 mmol), TEA (0.3 mL, 1.694 mmol) in DMF (4 mL)to afford the title compound (50 mg, 21%). LCMS: m/z: 571.3 (M+1)⁺.

Step 2: Preparation of2-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)benzamidehydrochloride

Using the same reaction conditions as described in step 8 of example 1,tert-butyl((1-(4-fluoro-2-((2-morpholinothiazolo[4,5-b]pyridin-6-yl)carbamoyl)phenyl)piperidin-4-yl)methyl)carbamate(50 mg, 0.087 mmol) was deprotected using methanolic HCl (4.7 mL) to getthe title compound (40 mg, 90%).

¹HNMR (DMSO-d₆, 300 MHz): δ 11.93 (s, 1H), 8.87-8.86 (d, 1H), 8.70-8.69(d, 1H), 8.20-7.98 (m, 3H), 7.65-7.61 (m, 1H), 7.49-7.43 (m, 2H),3.77-3.75 (t, 4H), 3.75-3.67 (t, 4H), 3.22-3.19 (m, 2H), 2.82-2.72 (m,4H), 1.89-1.85 (m, 3H), 1.40-1.36 (m, 2H). LCMS: 100%, m/z=471.3 (M+1)⁺.

HPLC: 96.8%.

Example 202-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Step 1: Preparation of 5-chlorothiazolo[4,5-b]pyridine-2-thiol

Using the same reaction conditions as described in step 1 of example 1,3-bromo-6-chloropyridin-2-amine (1.8 g, 8.653 mmol) was cyclised usingpotassium ethyl xanthate (2.35 g, 14.71 mmol) in in NMP (5 mL) at 165°C. for overnight to afford the crude product (2.0 g).

LCMS: m/z: 202.9 (M+1)⁺.

Step 2: Preparation of 5-chloro-2-(methylthio)thiazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 2 of example 1,5-chlorothiazolo[4,5-b]pyridine-2-thiol (2 g, 9.850 mmol) was methylatedusing potassium carbonate (2.71 g, 19.7 mmol) and methyl iodide (2.1 g,14.775 mmol) in ethyl acetate (10 mL) to afford the crude product. Theresultant crude was purified by 60-120 silica gel column chromatographyusing 20% ethyl acetate in hexane as eluent to obtain the title compound(500 mg, 23.8%).

¹HNMR (CDCl₃, 300 MHz): δ 8.02-8.00 (d, 1H), 7.37-7.24 (m, 2H), 2.85 (s,3H).

Step 3: Preparation of 4-(5-chlorothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 3 of example 15-chloro-2-(methylthio)thiazolo[4,5-b]pyridine (500 mg, 2.314 mmol) wassubstituted using morpholine (1 mL) and THF (1 mL) to afford the titlecompound (450 mg, 76.2%).

¹HNMR (CDCl₃, 400 MHz): δ 7.82-7.80 (d, 1H), 7.04-7.01 (d, 1H),3.84-3.83 (m, 4H), 3.75-3.71 (m, 4H). LCMS: m/z: 256.0 (M+1)⁺.

Step 4: Preparation of4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Potassium nitrate (266 mg, 2.64 mmol) was added to a solution of4-(5-chlorothiazolo[4,5-b]pyridin-2-yl)morpholine (450 mg, 1.764 mmol)in cone. sulphuric acid (5 mL) and stirred at RT overnight. Ice waterwas added to the RM and filtered the solid to afford the title compound(450 mg, 86.0%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.06 (s, 1H), 3.75 (s, 8H). LCMS: m/z: 301.0(M+1)⁺.

Step 5: Preparation of4-(6-nitro-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 1 of example 64-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (450 mg, 1.50mmol) was substituted using piperidine (0.5 mL) in THF (5 mL) 75° C. for2 h to obtain the title compound (450 mg, 85.7%). LCMS: m/z: 350.1(M+1)⁺.

Step 6: Preparation of2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,4-(6-nitro-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine (400mg, 1.142 mmol) was reduced with zinc dust (600 mg, 9.136 mmol) andammonium chloride (1.0 g, 18.272 mmol) in THF/methanol/H₂O (10/2 mL/1mL) to get the crude product (400 mg). LCMS: m/z: 320.25 (M+1)⁺.

Step 7: Preparation of2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (100 mg,0.313 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (64 mg, 0.313 mmol)using EDCI.HCl (90 mg, 0.47 mmol), HOBt (64 mg, 0.47 mmol), DIPEA (101mg, 0.782 mmol) in DMF (5 mL) to afford the crude product. The resultantcrude was purified by prep HPLC to obtain the title compound (40 mg,47.5%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.80 (s, 1H), 9.21 (s, 1H), 8.90-8.88 (m,2H), 8.19 (s, 1H), 8.07-8.06 (m, 1H), 3.73-3.72 (t, 4H), 3.60-3.58 (t,4H), 3.03-2.90 (t, 4H), 2.66 (s, 3H), 1.88-1.79 (t, 4H), 1.65-1.58 (m,2H). LCMS: 90.4%, m/z=506.3 (M+1)⁺. HPLC: 92.6%.

Example 21N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (productof step 6 of example 20) (100 mg, 0.313 mmol) was coupled with6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid(intermediate 3) (90 mg, 0.313 mmol) using EDCI.HCl (90 mg, 0.47 mmol),HOBt (64 mg, 0.47 mmol), DIPEA (101 mg, 0.782 mmol) in DMF (5 mL) toafford the crude coupled product. Using the same reaction conditions asdescribed in step 8 of example 1, the above crude product wasdeprotected using methanolic HCl (5 mL) to get the crude compound. Theresultant crude was purified by prep HPLC to obtain the title compound(30 mg, 43.5%).

¹HNMR (DMSO-d₆, 400 MHz): δ 10.80 (s, 1H), 9.05 (s, 1H), 8.39 (s, 2H),8.05-7.98 (m, 3H), 3.73-3.58 (m, 8H), 2.99-2.90 (m, 4H), 1.75-1.68 (m,4H), 1.54-1.48 (m, 2H).

LCMS: 85.0%, m/z=491.3 (M+1)⁺. HPLC: 95.7%.

Example 22N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide

Step 1: Preparation of5-chloro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 3 of example 15-chloro-2-(methylthio)thiazolo[4,5-b]pyridine (450 mg, 2.314 mmol) wassubstituted using piperidine (1 mL) and THF (mL) at 75° C. for 2 h toafford the crude product (500 mg). LCMS: m/z: 254.0 (M+1)⁺.

Step 2: Preparation of5-chloro-6-nitro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridine

Potassium nitrate (71 mg, 2.657 mmol) was added to the solution of5-chloro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridine (450 mg, 1.771 mmol)in conc. sulphuric acid (5 mL) and stirred at RT overnight. The icewater was added to the RM and filtered the solid to afford the titlecompound (400 mg, 75.5%). LCMS: m/z: 299.0 (M+1)⁺.

Step 3: Preparation of6-nitro-2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 1 of example 6,5-chloro-6-nitro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridine (400 mg,1.337 mmol) was substituted using piperidine (2.0 mL) in THF (5 mL) 75°C. for 30 min to obtain the crude product (400 mg). LCMS: m/z: 348.1(M+1)⁺.

Step 4: Preparation of2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,6-nitro-2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridine (400 mg, 1.149mmol) was reduced with zinc dust (597 mg, 9.192 mmol) and ammoniumchloride (974 mg, 18.384 mmol) in THF (10 mL) to get the crude product(320 mg). LCMS: m/z: 318.1 (M+1)⁺.

Step 5: Preparation ofN-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide

Using the same reaction conditions as described in step 6 of example 1,2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (100 mg, 0.315mmol) was coupled with6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinic acid(intermediate 3) (77 mg, 0.378 mmol) using EDCI.HCl (90 mg, 0.472 mmol),HOBt (63 mg, 0.472 mmol), DIPEA (101 mg, 0.787 mmol) in DMF (5 mL) toafford the crude product (140 mg). LCMS: m/z: 573.3 (M+1)⁺.

Step 6: Preparation ofN-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide

Using the same reaction conditions as described in step 8 of example 1,N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide(140 mg, 0.244) was deprotected using methanolic HCl (5 mL) to get thecrude compound. The resultant crude was purified by prep HPLC to obtainthe title compound (40 mg, 32.3%).

¹HNMR (CD₃OD, 400 MHz): δ 8.94 (s, 1H), 8.74 (s, 2H), 8.17-8.03 (m, 3H),3.90-3.82 (m, 4H), 3.33-3.32 (m, 4H), 1.90-1.83 (m, 10H), 1.69-1.68 (m,2H). LCMS: 99.0%, m/z=489.5 (M+1)⁺.

HPLC: 96.2%.

Example 23N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of step 4of example 22) (100 mg, 0.315 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (77 mg, 0.378 mmol)using EDCI.HCl (90 mg, 0.472 mmol), HOBt (63 mg, 0.472 mmol), DIPEA (101mg, 0.787 mmol) in DMF (5 mL) to afford the crude product. The resultantcrude was purified by prep HPLC to obtain the title compound (45 mg,26.5%).

¹HNMR (CD₃OD, 400 MHz): δ 9.00 (s, 1H), 8.96-8.94 (d, 1H), 8.77 (s, 1H),8.59 (s, 1H), 8.52-8.50 (d, 1H), 3.90-3.81 (m, 4H), 3.50-3.41 (m, 4H),2.94 (s, 3H), 1.89-1.75 (m, 12H).

LCMS: 80.0%, m/z=504.2 (M+1)⁺. HPLC: 98.4%.

Example 24N-(2,5-dimorpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of 2,5-dimorpholino-6-nitrooxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 1 of example 4,5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of step 5of example 2) (175 mg, 0.6147 mmol) was heated with morpholine (2 mL) at110° C. for 3 h. The solvent was distilled to afford the crude product.The resultant crude was purified by 60-120 silica gel columnchromatography using 1% methanol in DCM as eluent to obtain the titlecompound (190 mg, 92.23%).

¹HNMR (CDCl₃, 300 MHz): δ 8.14 (s, 1H), 3.84-3.81 (m, 12H), 3.49-3.45(m, 4H). LCMS: m/z=336.0 (M+1)⁺.

Step 2: Preparation of 2,5-dimorpholinooxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,2,5-dimorpholino-6-nitrooxazolo[4,5-b]pyridine (190 mg, 0.5666 mmol) wasreduced with zinc dust (297 mg, 4.5329 mmol) and ammonium chloride (485mg, 9.0659 mmol) in THF/methanol/H₂O (10 mL/2 mL/1 mL) to get the titlecompound (150 mg, 86.70%).

¹HNMR (CDCl₃, 400 MHz): δ 6.97 (s, 1H), 3.87-3.66 (m, 14H), 3.12-3.10(t, 4H). LCMS: m/z=306.1 (M+1)⁺.

Step 3: Preparation ofN-(2,5-dimorpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride

Using the same reaction conditions as described in step 6 of example 1,2,5-dimorpholinooxazolo[4,5-b]pyridin-6-amine (70 mg, 0.229 mmol), wascoupled with 2-(pyridin-4-yl)oxazole-4-carboxylic acid (56 mg, 0.275mmol) using EDCI.HCl (66 mg, 0.343 mmol), HOBt (47 mg, 0.343 mmol),DIPEA (0.16 mL, 0.917 mmol) in DMF (2 mL) to get the crude product. Thiswas then treated with methanolic HCl to afford the title compound (61mg, 50.41%).

¹HNMR (CD₃OD, 400 MHz): δ 8.90-8.88 (m, 2H), 8.7 (s, 1H), 8.6 (s, 1H),8.5 (d, 1H), 3.99-3.95 (t, 4H), 3.84-3.83 (t, 4H), 3.78-3.76 (t, 4H),3.20-3.18 (t, 4H), 2.92 (s, 3H). LCMS: m/z=492.0 (M+1)⁺. HPLC: 95.10%.

Example 25N-(5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of5-(4-methylpiperazin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 1 of example 4,5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of step 5of example 2) (175 mg, 0.6147 mmol) was heated with N-methylpiperazine(185 mg, 1.844 mmol) at 75° C. for 3 h. The solvent was distilled toafford the crude product. The resultant crude was purified by 60-120silica gel column chromatography using 5% methanol in DCM as eluent toobtain the title compound (200 mg, 93.45%). m/z=349.3 (M+1)⁺.

Step 2: Preparation of5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,5-(4-methylpiperazin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine(200 mg, 0.5747 mmol) was reduced with zinc dust (301 mg, 4.5977 mmol)and ammonium chloride (492 mg, 9.1954 mmol) in THF/methanol/H₂O (10 mL/2mL/1 mL) to get the title compound (150 mg, 81.96%). LCMS: m/z=319.4(M+1)⁺.

Step 3: Preparation ofN-(5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride

Using the same reaction conditions as described in step 6 of example 1,5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (70mg, 0.2198 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (54 mg, 0.2638 mmol)using EDCI.HCl (64 mg, 0.3298 mmol), HOBt (45 mg, 0.3298 mmol), DIPEA(0.145 mL, 0.8794 mmol) in DMF (2 mL) to get the crude product. This wasthen purified by prep HPLC and treated with methanolic HCl to afford thetitle compound (50 mg, 42.01%).

¹HNMR (CD₃OD, 400 MHz): δ 8.91 (m, 2H), 8.70 (s, 1H), 8.60-8.55 (m, 2H),3.85-3.82 (t, 4H), 3.76-3.74 (t, 4H), 3.67-3.30 (m, 8H), 3.04 (s, 3H),2.93 (s, 3H). m/z=505.3 (M+1)⁺. HPLC: 97.92%.

Example 26N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of step 4of example 4) (70 mg, 0.2317 mmol), was coupled with2-(6-methoxypyridin-3-yl)oxazole-4-carboxylic acid (intermediate 7) (62mg, 0.2781 mmol) using EDCI.HCl (67 mg, 0.3476 mmol), HOBt (47 mg,0.3476 mmol), DIPEA (0.162 mL, 0.9271 mmol) in DMF (2 mL) to afford thecrude product. This was then purified by prep HPLC to get the titlecompound (10 mg, 8.54%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.77 (s, 1H), 8.84 (s, 1H), 8.85-8.84 (d,1H), 8.60 (s, 1H), 8.27-8.24 (dd, 1H), 7.10-7.07 (d, 1H), 3.95 (s, 3H),3.62-3.60 (t, 4H), 2.94-2.91 (t, 4H), 1.90 (s, 4H), 1.77-1.50 (s, 8H).LCMS: m/z=504.2 (M+1)⁺. HPLC: 97.23%.

Example 27N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of step 4of example 4) (70 mg, 0.2317 mmol), was coupled with2-(2-methylpyridin-3-yl)oxazole-4-carboxylic acid (intermediate 8) (57mg, 0.2781 mmol) using EDCI.HCl (67 mg, 0.3476 mmol), HOBt (47 mg,0.3476 mmol), DIPEA (0.162 mL, 0.9271 mmol) in DMF (2 mL) to afford thecrude product. This was then purified by prep HPLC to get the titlecompound (50 mg, 44.24%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.79 (s, 1H), 9.02 (s, 1H), 8.639-8.631 (d,2H), 8.33-8.30 (d, 1H), 7.50-7.45 (m, 1H), 3.61-3.60 (m, 4H), 2.97 (s,3H), 2.90-2.88 (t, 4H), 1.80-1.70 (m, 4H), 1.61-1.50 (m, 8H). LCMS:m/z=488.2 (M+1)⁺. HPLC: 97.55%.

Example 28N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-hydroxypyridin-3-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of step 4of example 4) (70 mg, 0.232 mmol), was coupled with2-(2-hydroxypyridin-3-yl)oxazole-4-carboxylic acid (intermediate 9) (48mg, 0.232 mmol) using EDCI.HCl (67 mg, 0.348 mmol), HOBt (47 mg, 0.348mmol), DIPEA (75 mg, 0.581 mmol) in DMF (2 mL) to afford the titlecompound (75 mg, 66.3%).

¹HNMR (DMSO-d₆, 400 MHz): δ 12.4 (s, 1H), 9.80 (s, 1H), 8.87 (s, 1H),8.61 (s, 1H), 8.22-8.20 (d, 1H), 7.70-7.69 (d, 1H), 6.45-6.42 (t, 1H),3.62 (s, 4H), 2.90-2.89 (m, 4H), 1.90-1.77 (m, 4H), 1.69-1.55 (m, 8H).LCMS: m/z=490.1 (M+1)⁺. HPLC: 90.22%.

Example 292-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product ofstep 2 of example 6) (70 mg, 0.232 mmol), was coupled with2-(2-hydroxypyridin-3-yl)oxazole-4-carboxylic acid (intermediate 9) (48mg, 0.232 mmol) using EDCI.HCl (67 mg, 0.348 mmol), HOBt (47 mg, 0.348mmol), DIPEA (75 mg, 0.581 mmol) in DMF (2 mL) to afford the titlecompound (65 mg, 57.5%).

¹HNMR (DMSO-d₆, 400 MHz): δ 12.30 (s, 1H), 9.80 (s, 1H), 8.88 (s, 1H),8.65 (s, 1H), 8.24-8.13 (d, 1H), 7.70-7.64 (d, 1H), 6.50-6.30 (t, 1H),3.73-3.72 (m, 4H), 3.63-3.62 (m, 4H), 2.90-2.89 (m, 4H), 1.90-1.76 (m,4H), 1.64-1.54 (m, 2H). LCMS: m/z=492.0 (M+1)⁺. HPLC: 90.53%.

Example 30N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-hydroxypyridin-3-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of step 4of example 4) (75 mg, 0.247 mmol), was coupled with2-(2-hydroxypyridin-5-yl)oxazole-4-carboxylic acid (intermediate 10) (61mg, 0.297 mmol) using EDCI.HCl (70 mg, 0.371 mmol), HOBt (50 mg, 0.371mmol), DIPEA (0.2 mL, 0.99 mmol) in DMF (4 mL) to afford the crudeproduct. This was then purified by prep HPLC to get the title compound(25 mg, 21%).

¹HNMR (DMSO-d₆, 400 MHz): δ 12.30 (s, 1H), 9.90 (s, 1H), 8.84 (s, 1H),8.59 (s, 1H), 8.14-8.02 (d, 1H), 7.98-7.88 (d, 1H), 6.68-6.53 (d, 1H),3.64-3.52 (m, 4H), 2.94-2.92 (t, 4H), 1.84-1.73 (m, 4H), 1.70-1.54 (m,8H). LCMS: m/z=490.2 (M+1)⁺. HPLC: 93.74%.

Example 312-(2-methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product ofstep 2 of example 6) (70 mg, 0.230 mmol), was coupled with2-(2-methoxypyridin-4-yl)oxazole-4-carboxylic acid (intermediate 11) (57mg, 0.276 mmol) using EDCI.HCl (67 mg, 0.346 mmol), HOBt (47 mg, 0.346mmol), DIPEA (0.161 mL, 0.929 mmol) in DMF (2 mL) to afford the crudeproduct. This was then purified by prep HPLC to get the title compound(7 mg, 6.03%).

¹HNMR (CDCl₃, 400 MHz): δ 10.0 (s, 1H), 8.76 (s, 1H), 8.38-8.33 (d, 2H),7.51 (s, 1H), 7.38 (s, 1H), 5.34 (s, 1H), 4.10 (s, 3H), 3.80-3.70 (d,8H), 3.05 (s, 4H), 1.89-1.82 (m, 4H), 1.65-1.63 (bs, 2H). LCMS:m/z=506.2 (M+1)⁺. HPLC: 95.81%.

Example 322-(2-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product ofstep 2 of example 6) (70 mg, 0.230 mmol), was coupled with2-(2-methoxypyridin-3-yl)oxazole-4-carboxylic acid (intermediate 8) (57mg, 0.276 mmol) using EDCI.HCl (67 mg, 0.346 mmol), HOBt (47 mg, 0.346mmol), DIPEA (0.161 mL, 0.929 mmol) in DMF (2 mL) to afford the crudeproduct. This was then purified by prep HPLC to get the title compound(7 mg, 6.03%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.91 (s, 1H), 9.11 (s, 1H), 8.78-8.77 (d,1H), 8.65-8.62 (m, 2H), 7.76-7.75 (t, 1H), 3.73-3.61 (m, 8H), 3.08 (s,3H), 2.94-2.75 (m, 4H), 1.76-1.65 (m, 4H), 1.60-1.55 (m, 2H). LCMS:m/z=490.2 (M+1)⁺. HPLC: 96.28%.

Example 332-(3-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product ofstep 2 of example 6) (54 mg, 0.265 mmol), was coupled with2-(3-methylpyridin-4-yl)oxazole-4-carboxylic acid (intermediate 12) (80mg, 0.265 mmol) using EDCI.HCl (77 mg, 0.397 mmol), HOBt (38 mg, 0.278mmol), DIPEA (0.12 mL, 0.927 mmol) in DMF (5 mL) to afford the titlecompound (121 mg, 93%).

¹HNMR (DMSO-d₆, 300 MHz): δ 9.90 (s, 1H), 9.10 (s, 1H), 8.75-8.60 (m,3H), 7.95-7.86 (d, 1H), 3.80-3.52 (m, 8H), 2.95-2.85 (m, 4H), 2.80 (s,3H), 1.80-1.68 (m, 4H), 1.66-1.50 (m, 2H).

LCMS: m/z=490.4 (M+1)⁺. HPLC: 95.93%.

Example 34N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(3-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of step 4of example 4) (54 mg, 0.265 mmol), was coupled with2-(3-methylpyridin-4-yl)oxazole-4-carboxylic acid (intermediate 12) (80mg, 0.265 mmol) using EDCI.HCl (77 mg, 0.397 mmol), HOBt (38 mg, 0.278mmol), DIPEA (0.12 mL, 0.927 mmol) in DMF (5 mL) to afford the titlecompound (117 mg, 91%).

¹HNMR (DMSO-d₆, 300 MHz): δ 9.90 (s, 1H), 9.05 (s, 1H), 8.77 (s, 1H),8.68-8.60 (m, 2H), 7.90-7.85 (d, 1H), 3.70-3.60 (m, 4H), 2.95-2.85 (m,4H), 2.80 (s, 3H), 1.80-1.70 (m, 4H), 1.68-1.50 (m, 8H). LCMS: 98.99%,m/z=488.4 (M+1)⁺. HPLC: 97.00%.

Example 352-(6-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product ofstep 2 of example 6) (70 mg, 0.230 mmol), was coupled with2-(6-methylpyridin-3-yl)oxazole-4-carboxylic acid (intermediate 13) (57mg, 0.276 mmol) using EDCI.HCl (67 mg, 0.346 mmol), HOBt (47 mg, 0.346mmol), DIPEA (0.201 mL, 1.153 mmol) in DMF (2 mL) to afford crudeproduct. This was then purified by prep HPLC to get the title compound(30 mg, 24.79%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.85 (s, 1H), 9.147-9.142 (d, 1H), 9.04 (s,1H), 8.64 (s, 1H), 8.37-8.35 (dd, 1H), 7.64-7.62 (d, 1H), 3.74-3.72 (m,4H), 3.64-3.62 (m, 4H), 3.15-2.90 (m, 4H), 2.62 (s, 3H), 1.90-1.75 (m,4H), 1.70-1.55 (m, 2H). LCMS: 98.39%, m/z=490.0 (M+1)⁺.

HPLC: 95.97%.

Example 366-(1-methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product ofstep 2 of example 6) (80 mg, 0.2640 mmol), was coupled with6-(1-methyl-1H-pyrazol-4-yl)picolinic acid (intermediate 4) (65 mg,0.3168 mmol) using EDCI.HCl (76 mg, 0.3960 mmol), HOBt (38 mg, 0.2772mmol), DIPEA (0.103 mg, 0.7920 mmol) in DMF (4 mL) to afford titlecompound (75 mg, 58.59%).

¹HNMR (DMSO-d₆, 400 MHz): δ 10.9 (s, 1H), 8.70 (s, 1H), 8.43 (s, 1H),8.22 (s, 1H), 8.10-7.90 (m, 3H), 4.00 (s, 3H), 3.80-3.70 (m, 4H),3.69-3.60 (m, 4H), 3.0 (s, 4H), 1.80 (s, 4H), 1.55 (s, 2H).

LCMS: 100%, m/z=489.3 (M+1)⁺. HPLC: 96.26%.

Example 37N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methylpyridin-3-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product of step 4of example 4) (80 mg, 0.265 mmol), was coupled with2-(2-methylpyridin-5-yl)oxazole-5-carboxylic acid (intermediate 13) (60mg, 0.292 mmol) using EDCI.HCl (77 mg, 0.398 mmol), HOBt (38 mg, 0.279mmol), DIPEA (0.102 mg, 0.797 mmol) in DMF (4 mL) to afford the titlecompound (90 mg, 69.7%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.83 (s, 1H), 9.11 (s, 1H), 9.00 (s, 1H),8.61 (s, 1H), 8.27-8.25 (dd, 1H), 7.54-7.52 (d, 1H), 3.63 (s, 4H),2.94-2.93 (t, 4H), 2.58 (s, 3H), 1.82 (s, 4H), 1.63 (s, 8H).

LCMS: 98.89%, m/z=488.2 (M+1)⁺. HPLC: 98.54%.

Example 38(S)—N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of tert-butyl(S)-(1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate

In a round bottom flask, taken5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of step 5of example 2) (157 mg, 0.555 mmol), tert-butyl(S)-pyrrolidin-3-ylcarbamate (125 mg, 0.555 mmol) potassium carbonate(238 mg, 1.722 mmol) and DMF (5 mL) and stirred at RT overnight. The icewater was added and filtered the solid and dried under vacuum to affordthe crude product which was used as such for next step.

LCMS: m/z=435.2 (M+1)⁺. HPLC: 80.36%.

Step 2: Preparation of tert-butyl(S)-(1-(6-amino-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate

The crude tert-butyl(S)-(1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamateobtained above was dissolved in methanol (30 mL) and added 10% Pd/C (25mg) and stirred under hydrogen balloon for two hours. The reaction masswas filtered through Celite® and concentrated to get the title compound(71 mg, 32%).

LCMS: m/z=405.2 (M+1)⁺. HPLC: 79.86%.

Step 3: Preparation of tert-butyl(S)-(1-(6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate

Using the same reaction conditions as described in step 6 of example 1,tert-butyl(S)-(1-(6-amino-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate(70 mg, 0.341 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (115 mg, 0.284 mmol)using EDCI.HCl (98 mg, 0.512 mmol), HOBt (46 mg, 0.341 mmol), DIPEA(0.148 mg, 1.1384 mmol) in DMF (4 mL) to get the title compound (152 mg,91%).

LCMS: m/z=591.6 (M+1)⁺. HPLC: 86.43%.

Step 4: Preparation of(S)—N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride

Using the same reaction conditions as described in step 8 of example 1,tert-butyl(S)-(1-(6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morphlinooxaolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate(150 mg, 0.2542 mmol) was deprotected using methanolic HCl (5 mL) to getthe crude product. This was then purified by prep HPLC to get the titlecompound (58 mg, 97%).

¹HNMR (CD₃OD, 400 MHz): δ 8.97 (s, 1H), 8.93-8.91 (d, 1H), 8.64 (s, 1H),8.56-8.55 (d, 1H), 8.02 (s, 1H), 4.02-3.67 (m, 13H), 2.90 (s, 3H),2.50-2.40 (m, 1H), 2.25-2.05 (m, 1H).

LCMS: 96.74%, m/z=491.4 (M+1)⁺. HPLC: 95.27%.

Example 39(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of(S)-1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol

Using the same reaction conditions as described in step 1 of example 38,5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of step 5of example 2) (200 mg, 0.704 mmol) was substitutedwith(S)-pyrrolidin-3-ol (61 mg, 0.704 mmol) using potassium carbonate(291 mg, 2.112 mmol) and DMF (5 mL) to afford the title product (195 mg,82%) LCMS: m/z=335.9 (M+1)⁺.

Step 2: Preparation of(S)-1-(6-amino-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol

Using the same reaction conditions as described in step 2 of example 38,(S)-1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol(194 mg, 0.579 mmol) was reduced using 10% Pd/C (50 mg) in methanol (40mL) to get the title compound (162 mg, 92%). LCMS: m/z=306.1 (M+1)⁺.

Step 3: Preparation of(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,(S)-1-(6-amino-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol(160 mg, 0.526 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (108 mg, 0.526 mmol)using EDCI.HCl (151 mg, 0.789 mmol), HOBt (75 mg, 0.5523 mmol), DIPEA(0.272 mg, 2.104 mmol) in DMF (5 mL) to get the title compound (45 mg,17%).

¹HNMR (CD₃OD, 400 MHz): δ 8.70 (s, 1H), 8.64-8.63 (d, 1H), 8.02 (s, 1H),7.94-7.93 (d, 1H), 7.87 (s, 1H), 4.49-4.45 (m, 1H), 3.84-3.71 (m, 10H),3.70-3.47 (m, 2H), 2.67 (s, 3H), 2.13-2.10 (m, 1H), 2.00-1.80 (m, 1H).LCMS: 100%, m/z=492.2 (M+1)⁺. HPLC: 97.90%.

Example 40(R)—N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of tert-butyl(R)-(1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate

Using the same reaction conditions as described in step 1 of example 38,5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of step 5of example 2) (126 mg, 0.444 mmol) was substituted with tert-butyl(R)-pyrrolidin-3-ylcarbamate (100 mg, 0.444 mmol) using potassiumcarbonate (183 mg, 1.33 mmol) and DMF (5 mL) to afford the crudeproduct. The resultant crude was purified by 60-120 silica gel columnchromatography using 1% methanol in DCM as eluent to obtain the titlecompound (127 mg, 66%). LCMS: m/z=435.2 (M+1)⁺.

Step 2: Preparation of tert-butyl(R)-(1-(6-amino-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate

Using the same reaction conditions as described in step 2 of example 38,(R)-(1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate(126 mg, 0.290 mmol) was reduced using 10% Pd/C (25 mg) in methanol (20mL) to get the title compound (102 mg, 87%).

LCMS: m/z=405.3 (M+1)⁺.

Step 3: Preparation of tert-butyl(R)-(1-(6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate

Using the same reaction conditions as described in step 6 of example 1,tert-butyl(R)-(1-(6-amino-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate(100 mg, 0.2475 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (51 mg, 0.2475 mmol)using EDCI.HCl (72 mg, 0.3712 mmol), HOBt (35 mg, 0.2599 mmol), DIPEA(0.128 mg, 0.990 mmol) in DMF (5 mL) to get the title compound (73 mg,51%). LCMS: m/z=591.1 (M+1)⁺.

Step 4: Preparation of(R)—N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride

Using the same reaction conditions as described in step 8 of example 1,tert-butyl(R)-(1-(6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate(73 mg, 0.123 mmol) was deprotected using methanolic HCl (5 mL) to getthe title compound (32 mg, 53%).

¹HNMR (CD₃OD, 400 MHz): δ 9.72 (s, 1H), 8.65-8.63 (d, 1H), 8.01 (s, 1H),7.93-7.90 (t, 2H), 3.84-3.81 (t, 4H), 3.70-3.64 (m, 7H), 3.60-3.50 (m,2H), 2.67 (s, 3H), 2.30-2.20 (m, 1H), 1.90-1.80 (m, 1H). LCMS: 96.75%,m/z=491.2 (M+1)⁺. HPLC: 95.80%.

Example 41(R)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of(R)-1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol

Using the same reaction conditions as described in step 1 of example 38,5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of step 5of example 2) (200 mg, 0.704 mmol) was substituted with(R)-pyrrolidin-3-ol (61 mg, 0.704 mmol) using potassium carbonate (291mg, 2.112 mmol) and DMF (5 mL) to afford the title product (231 mg,98.7%). LCMS: m/z=336.1 (M+1)⁺.

Step 2: Preparation of(R)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine

To the solution of(R)-1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol(230 mg, 0.698 mmol) in DMF (5 mL) was added TBDMS chloride (124 mg,0.822 mmol) and imidazole (116 mg, 1.70 mmol) and stirred at RTovernight. Reaction mass was quenched with water and extracted withethyl acetate to get the crude product. The resultant crude was purifiedby 60-120 silica gel column chromatography using 1% methanol in DCM aseluent to obtain the title compound (310 mg, 99%). LCMS: m/z=450.3(M+1)⁺.

Step 3: Preparation of(R)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 2 of example 38,(R)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine(308 mg, 0.685 mmol) was reduced using 10% Pd/C (30 mg) in methanol (20mL) to get the title compound (235 mg, 81%). LCMS: m/z=420.2 (M+1)⁺.

Step 4: Preparation of(R)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,(R)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine(234 mg, 0.5587 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (114 mg, 0.5584 mmol)using EDCI.HCl (180 mg, 0.840 mmol), HOBt (81 mg, 0.5863 mmol), DIPEA(0.290 mg, 2.237 mmol) in DMF (5 mL) to get the title compound (167 mg,50%). LCMS: m/z=606.2 (M+1)⁺.

Step 5: Preparation of(R)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 8 of example 1,(R)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide(167 mg, 0.276 mmol) was deprotected using methanolic HCl (5 mL) to getthe title compound (106 mg, 78%).

¹HNMR (DMSO-d₆, 300 MHz): δ 9.82 (s, 1H), 8.96 (s, 1H), 8.68-8.67 (d,1H), 7.86 (s, 1H), 7.80-7.77 (d, 1H), 7.66 (s, 1H), 4.86 (s, 1H), 4.27(s, 1H), 3.72-3.6.0 (m, 11H), 3.25-3.21 (m, 1H), 2.58 (s, 3H), 1.89-1.78(m, 2H). LCMS: 98.95%, m/z=492.2 (M+1)⁺. HPLC: 95.08%.

Example 42(S)-2-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Step 1: Preparation of tert-butyl(S)-(1-(4-((2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)carbamoyl)oxazol-2-yl)pyrrolidin-3-yl)carbamate

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product ofstep 2 of example 6) (100 mg, 0.3296 mmol), was coupled with(S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylicacid (intermediate 14) (147 mg, 0.4944 mmol) using EDCI.HCl (95 mg,0.4944 mmol), HOBt (67 mg, 0.4944 mmol), DIPEA (0.23 mL, 1.3185 mmol) inDMF (2 mL) to afford crude product. The resultant crude was purified by60-120 silica gel column chromatography using 1% methanol in DCM aseluent to obtain the title compound (130 mg, 67.7%). LCMS: m/z=583.5(M+1)⁺.

Step 2: Preparation of(S)-2-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 8 of example 1,tert-butyl(S)-(1-(4-((2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)carbamoyl)oxazol-2-yl)pyrrolidin-3-yl)carbamate(130 mg, 4.482 mmol) was deprotected using TFA (5 mL) and DCM (5 mL) toget the title compound (73 mg, 68.22%).

¹HNMR (CDCl₃, 400 MHz): δ 9.90 (s, 1H), 8.77 (s, 1H), 7.82 (s, 1H),3.81-3.73 (m, 10H), 3.69-3.59 (m, 1H), 3.38-3.28 (m, 1H), 3.02 (s, 4H),2.30-2.15 (m, 1H), 1.82 (m, 5H), 1.70-1.60 (m, 3H).

LCMS: 99.52%, m/z=483.2 (M+1)⁺. HPLC: 98.70%.

Example 43(S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide

Step 1: Preparation of6-bromo-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product ofstep 2 of example 6) (400 mg, 1.3245 mmol), was coupled with6-bromopicolinic acid (321 mg, 1.5894 mmol) using EDCI.HCl (321 mg,1.9867 mmol), HOBt (268 mg, 1.9867 mmol), DIPEA (683 mg, 5.2980 mmol) inDMF (20 mL) to afford the title compound (487 mg, 75%).

¹HNMR (CDCl₃, 400 MHz): δ 10.86 (s, 1H), 8.82 (s, 1H), 8.24-8.22 (d,1H), 7.80-7.86 (t, 1H), 7.67-7.65 (d, 1H), 3.83-3.73 (m, 8H), 3.06-3.03(t, 4H), 1.90-1.88 (m, 4H), 1.70-1.60 (m, 2H).

LCMS: m/z=489.1 (M+2)⁺. HPLC: 97.69%.

Step 2: Preparation of(S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide

The mixture of6-bromo-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide(130 mg, 0.2269 mmol), (S)-pyrrolidin-3-ol (35 mg, 0.4 mmol) and sodiumcarbonate (85 mg, 0.8 mmol) in DMF (2 mL) was heated at 140° C. for 12h. The reaction was quenched with ice water, filtered and purified by60-120 silica gel column chromatography using 1% methanol in DCM aseluent to obtain the title compound (80 mg, 60.79%).

¹HNMR (CDCl₃, 400 MHz): δ 10.66 (s, 1H), 8.83 (s, 1H), 7.64-7.62 (t,1H), 7.58-7.56 (d, 1H), 6.58-6.56 (d, 1H), 3.83-3.79 (m, 4H), 3.76-3.72(m, 7H), 3.04-3.03 (m, 4H), 2.30-2.10 (m, 2H), 1.77-1.72 (m, 4H),1.61-1.57 (m, 3H). LCMS: 96.72%, m/z=494.2 (M+1)⁺. HPLC: 98.60%.

Example 44(S)-6-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide

Step 1: Preparation of tert-butyl(S)-(1-(6-((2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate

Using the same reaction conditions as described in step 2 of example 43,6-bromo-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide(product of step 2 of example 6) (100 mg, 0.2053 mmol) was substitutedwith tert-butyl (S)-pyrrolidin-3-ylcarbamate (57 mg, 0.3080 mmol) usingsodium carbonate (65 mg, 0.6160 mmol) in DMF (2 mL) at 140° C. for 12 hto obtain the title compound (60 mg, 49.34%).

Step 2: Preparation of(S)-6-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide

Using the same reaction conditions as described in step 8 of example 1,tert-butyl(S)-(1-(6-((2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(60 mg, 0.1013 mmol) was deprotected using TFA (2 mL) and DCM (2 mL) toget the title compound (30 mg, 60.16%).

¹HNMR (CDCl₃, 400 MHz): δ 10.70 (s, 1H), 8.84 (s, 1H), 7.65-7.61 (t,1H), 7.57-7.55 (d, 1H), 6.56-6.54 (d, 1H), 3.87-3.63 (m, 9H), 3.39-3.37(m, 1H), 3.04-3.01 (t, 4H), 2.28-2.25 (m, 2H), 1.90-1.87 (m, 1H),1.771-1.76 (m, 5H), 1.60-1.56 (m, 3H).

LCMS: 98.72%, m/z=493.3 (M+1)⁺. HPLC: 97.84%.

Example 45(S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product ofstep 2 of example 6) (100 mg, 0.3296 mmol), was coupled with(S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylicacid (intermediate 15) (124 mg, 0.3955 mmol) using EDCI.HCl (95 mg,0.4944 mmol), HOBt (67 mg, 0.4944 mmol), DIPEA (0.23 mL, 1.3185 mmol) inDMF (2 mL) to afford crude product. Using the same reaction conditionsas described in step 8 of example 1, this crude product was deprotectedusing methanolic HCl (5 mL) to get the title compound (128 mg, 80.5%).

¹HNMR (CDCl₃, 300 MHz): δ 9.78 (s, 1H), 8.76 (s, 1H), 7.82 (s, 1H),4.70-4.60 (m, 1H), 3.82-3.56 (m, 12H), 3.03-3.00 (t, 4H), 2.19-2.11 (m,2H), 1.81-1.78 (m, 6H). LCMS: 95.04%, m/z=484.2 (M+1)⁺. HPLC: 95.55%.

Example 46(S)—N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in example 45,5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-amine (product of step7 of example 2) (100 mg, 0.384 mmol), was coupled with(S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylicacid (intermediate 15) (145 mg, 0.4615 mmol) using EDCI.HCl (110 mg,0.5769 mmol), HOBt (78 mg, 0.5769 mmol), DIPEA (0.268 mL, 1.5384 mmol)in DMF (2 mL) followed by deprotection using methanolic HCl (5 mL) toget the title compound (56 mg, 50.4%).

¹HNMR (CDCl₃, 300 MHz): δ 9.17 (s, 1H), 8.33 (s, 1H), 7.84 (s, 1H),4.70-4.60 (m, 1H), 3.82-3.56 (m, 12H), 2.13-2.03 (m, 3H), 1.86-1.84 (d,1H), 1.16-1.13 (m, 2H), 1.04-1.00 (m, 2H).

LCMS: 93.32%, m/z=440.8 (M+1)⁺. HPLC: 95.51%.

Example 47(S)-2-(3-aminopyrrolidin-1-yl)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in example 45,5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-amine (product of step7 of example 2) (100 mg, 0.384 mmol), was coupled with(S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylicacid (intermediate 14) (137 mg, 0.4615 mmol) using EDCI.HCl (110 mg,0.5769 mmol), HOBt (78 mg, 0.5769 mmol), DIPEA (0.268 mL, 1.5384 mmol)in DMF (2 mL) followed by deprotection using TFA (5 mL) and DCM (5 mL)to get the title compound (27 mg, 18.49%).

¹HNMR (CDCl₃, 400 MHz): δ 9.17 (s, 1H), 8.34 (s, 1H), 7.83 (s, 1H),3.82-3.72 (m, 10H), 3.61-3.59 (m, 1H), 3.29-3.26 (m, 1H), 2.30-2.18 (m,2H), 2.10-2.00 (m, 1H), 1.90-1.78 (m, 1H), 1.16-1.15 (m, 2H), 1.04-1.00(m, 2H). LCMS: 100%, m/z=440.2 (M+1)⁺. HPLC: 98.06%.

Example 482-(2-methylpyridin-4-yl)-N-(5-(piperidin-1-yl)-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamidehydrochloride

Step 1: Preparation of5-chloro-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 3 of example 1,5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (250 mg) was substitutedusing pyrrolidine (2 mL) and THF (5 mL) at 75° C. for 2 h to afford thetitle compound (250 mg).

¹HNMR (CDCl₃, 400 MHz): δ 7.35-7.33 (d, 1H), 6.89-6.87 (d, 1H),3.70-3.60 (m, 4H), 2.10-2.00 (m, 4H). LCMS: m/z=224.1 (M+1)⁺.

Step 2: Preparation of5-chloro-6-nitro-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 4 of example 20,5-chloro-6-nitro-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine (250 mg,1.121 mmol) was nitrated using potassium nitrate (226 mg, 2.242 mmol)and conc. sulphuric acid (3 mL) at RT for 24 h to afford the crude titlecompound (180 mg, 60%).

Step 3: Preparation of6-nitro-5-(piperidin-1-yl)-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 1 of example 6,5-chloro-6-nitro-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine (180 mg,0.6716 mmol) was substituted using piperidine (57 mg) in THF (3 mL) atRT for 12 h to obtain the title compound (150 mg, 70.7%).

LCMS: m/z=318.45 (M+1)⁺.

Step 4: Preparation of5-(piperidin-1-yl)-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,6-nitro-5-(piperidin-1-yl)-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine(150 mg, 0.4731 mmol) was reduced with zinc dust (247 mg, 3.7854 mmol)and ammonium chloride (404 mg, 7.5696 mmol) in THF/methanol/H₂O (5 m/1mL/0.5 mL) to get the crude title product (152 mg). LCMS: m/z=288.2(M+1)⁺.

Step 5: Preparation of2-(2-methylpyridin-4-yl)-N-(5-(piperidin-1-yl)-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamidehydrochloride

Using the same reaction conditions as described in step 6 of example 1,5-(piperidin-1-yl)-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (150mg, 0.5226 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (127 mg, 0.6271 mmol)using EDCI.HCl (149 mg, 0.7839 mmol), HOBt (108 mg, 0.7839 mmol), DIPEA(0.18 mL, 1.0452 mmol) in DMF (2 mL) to afford the crude product. Theresultant crude was purified by prep HPLC and treated with methanolicHCl to obtain the title compound (38 mg, 14.28%).

¹HNMR (CDCl₃, 400 MHz): δ 13.4-12.8 (bs, 1H), 11.80 (s, 1H), 9.19 (s,1H), 8.74 (s, 1H), 8.47-8.42 (m, 2H), 7.93 (s, 1H), 3.74 (s, 4H), 3.65(s, 4H), 3.08 (s, 3H), 2.48 (s, 2H), 2.12 (s, 4H), 1.99 (s, 2H),1.90-1.70 (m, 2H). LCMS: 100%, m/z=474.2 (M+1)⁺. HPLC: 97.93%.

Example 49N-(2-(2,6-dimethylmorpholino)-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride

Step 1: Preparation of5-chloro-2-(2,6-dimethylmorpholino)oxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 3 of example 1,5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (product of step 3 example2) (250 mg, 1.25 mmol) was substituted using 2,6-dimethylmorpholine (2mL) and THF (5 mL) at 75° C. for 2 h to afford the title compound (251mg).

¹HNMR (CDCl₃, 400 MHz): δ 7.38-7.36 (d, 1H), 6.94-6.92 (d, 1H),4.17-4.14 (d, 2H), 3.75-3.68 (m, 2H), 2.90-2.84 (t, 2H), 1.27-1.26 (d,6H). LCMS: m/z=268.0 (M+1)⁺.

Step 2: Preparation of5-chloro-2-(2,6-dimethylmorpholino)-6-nitrooxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 4 of example 20,5-chloro-2-(2,6-dimethylmorpholino)oxazolo[4,5-b]pyridine (250 mg,0.9363 mmol) was nitrated using potassium nitrate (189 mg, 1.8726 mmol)and cone. sulphuric acid (3 mL) at RT for 24 h to afford the titlecompound (150 mg, 51.3%). LCMS: m/z=313.0 (M+1)⁺.

Step 3: Preparation of2-(2,6-dimethylmorpholino)-6-nitro-5-(piperidin-1-yl)oxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 1 of example 6,5-chloro-2-(2,6-dimethylmorpholino)-6-nitrooxazolo[4,5-b]pyridine (150mg, 0.1602 mmol) was substituted using piperidine (45 mg) in THF (3 mL)at RT for 12 h to obtain the title compound (152 mg, 86.2%).

LCMS: m/z=362.4 (M+1)⁺.

Step 4: Preparation of2-(2,6-dimethylmorpholino)-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,2-(2,6-dimethylmorpholino)-6-nitro-5-(piperidin-1-yl)oxazolo[4,5-b]pyridine(152 mg, 0.4143 mmol) was reduced with zinc dust (216 mg, 3.3147 mmol)and ammonium chloride (353 mg, 6.6288 mmol) in THF/methanol/H₂O (5 mL/1mL/0.5 mL) to get the crude title compound (160 mg). ¹HNMR (CDCl₃, 400MHz): δ 6.96 (s, 1H), 4.11-4.07 (dd, 2H), 3.74-3.70 (m, 2H), 3.02-3.01(m, 4H), 2.83-2.77 (t, 2H), 1.76-1.68 (m, 4H), 1.64-1.56 (m, 2H),1.26-1.24 (d, 6H). LCMS: m/z=332.2 (M+1)⁺.

Step 5: Preparation ofN-(2-(2,6-dimethylmorpholino)-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride

Using the same reaction conditions as described in step 6 of example 1,2-(2,6-dimethylmorpholino)-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine(152 mg, 0.6024 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (147 mg, 0.7228 mmol)using EDCI.HCl (172 mg, 0.9036 mmol), HOBt (125 mg, 0.9036 mmol), DIPEA(0.2 mL, 1.2048 mmol) in DMF (2 mL) to afford the crude product. Theresultant crude was purified by prep HPLC and treated with methanolicHCl to obtain the title compound (80 mg).

¹HNMR (CDCl₃, 400 MHz): δ 13.15-12.90 (bs, 1H), 11.90 (s, 1H), 9.18 (s,1H), 8.74 (s, 1H), 8.46-8.42 (d, 1H), 7.96 (s, 1H), 4.21-4.18 (m, 2H),3.76-3.60 (m, 6H), 3.08 (s, 3H), 2.99-2.92 (t, 2H), 2.60-2.41 (m, 2H),2.08-1.90 (m, 2H), 1.60-1.80 (m, 2H), 1.29-1.27 (d, 6H).

LCMS: 100%, m/z=518.5 (M+1)⁺. HPLC: 98.81%.

Example 50N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamidehydrochloride

Using the same reaction conditions as described in step 6 of example 1,2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of step 4of example 22) (70 mg, 0.220 mmol) was coupled6-(1-methyl-1H-pyrazol-4-yl)picolinic acid (intermediate 4) (53 mg,0.264 mmol) using EDCI.HCl (63 mg, 0.33 mmol), HOBt (45 mg, 0.33 mmol),DIPEA (78 mg, 0.66 mmol) in DMF (5 mL) to afford the crude product. Theresultant crude was purified by prep HPLC and treated with methanolicHCl to obtain the title compound (25 mg, 21.2%).

¹HNMR (CD₃OD, 300 MHz): δ 9.01 (s, 1H), 8.42 (s, 1H), 8.30 (s, 1H),8.10-8.01 (m, 2H), 7.92-7.89 (dd, 1H), 4.01 (s, 3H), 3.80 (s, 4H),3.39-3.30 (m, 4H), 1.82 (s, 10H), 1.69-1.67 (d, 2H).

LCMS: 98.92%, m/z=503.3 (M+1)⁺. HPLC: 98.03%.

Example 516-(1-methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (productof step 6 of example 20) (70 mg, 0.313 mmol) was coupled with6-(1-methyl-1H-pyrazol-4-yl)picolinic acid (intermediate 4) (53 mg,0.262 mmol) using EDCI.HCl (62 mg, 0.327 mmol), HOBt (45 mg, 0.327mmol), DIPEA (85 mg, 0.654 mmol) in DMF (5 mL) to afford the crudecoupled product. The resultant crude was purified by prep HPLC to obtainthe title compound (35 mg, 30%).

¹HNMR (CD₃OD, 300 MHz): δ 8.96 (bs, 1H), 8.46 (s, 1H), 8.34 (s, 1H),8.11-8.01 (m, 2H), 7.94-7.91 (d, 1H), 4.02 (s, 3H), 3.88-3.82 (m, 8H),3.55-3.21 (m, 4H), 1.87 (s, 4H), 1.80-1.60 (m, 2H).

LCMS: 82.87%, m/z=505.2 (M+1)⁺. HPLC: 97.63%.

Example 52N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazole-4-carboxamidehydrochloride

Using the same reaction conditions as described in step 6 of example 1,2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of step 4of example 22) (70 mg, 0.220 mmol) was coupled with2-(2-methylpyridin-3-yl)oxazole-4-carboxylic acid (intermediate 8) (50mg, 0.242 mmol) using EDCI.HCl (63 mg, 0.33 mmol), HOBt (45 mg, 0.33mmol), DIPEA (85 mg, 0.66 mmol) in DMF (5 mL) to afford the crudeproduct. The resultant crude was purified by prep HPLC and treated withmethanolic HCl to obtain the title compound (30 mg, 27.2%).

¹HNMR (CD₃OD, 400 MHz): δ 9.21-9.19 (d, 2H), 8.91-8.88 (m, 3H), 8.80(bs, 1H), 8.15-8.11 (t, 2H), 3.78 (s, 8H), 3.18 (s, 3H), 1.80 (s, 8H),1.71-1.70 (m, 4H). LCMS: 85.44%, m/z=504.2 (M+1)⁺. HPLC: 98.54%.

Example 53N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of (2R,6S)-4-(5-chlorothiazolo[4,5-b]pyridin-2-yl)-2,6-dimethylmorpholine

Using the same reaction conditions as described in step 3 of example 1,5-chloro-2-(methylthio)thiazolo[4,5-b]pyridine (product of step 2 ofexample 20) (170 mg, 0.784 mmol) was substituted using(2R,6S)-2,6-dimethylmorpholine (1 mL) and THF (2 mL) at 75° C. for 16 hto afford the crude title compound (260 mg). LCMS: m/z=284.1 (M+1)⁺.

Step 2: Preparation of(2R,6S)-4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)-2,6-dimethylmorpholine

Using the same reaction conditions as described in step 4 of example 20,(2R,6S)-4-(5-chlorothiazolo[4,5-b]pyridin-2-yl)-2,6-dimethylmorpholine(260 mg, 0.916 mmol) was nitrated using potassium nitrate (277 mg, 2.74mmol) and conc. sulphuric acid (5 mL) at RT for 2 days to afford thecrude title compound (120 mg). LCMS: m/z=328.9 (M+1)⁺.

Step 3: Preparation of(2R,6S)-2,6-dimethyl-4-(6-nitro-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 1 of example 6,(2R,6S)-4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)-2,6-dimethylmorpholine(120 mg, 0.365 mmol) was substituted using piperidine (0.5 mL) in THF (2mL) at RT for 30 min to obtain the title compound (190 mg). m/z=378.0(M+1)⁺.

Step 4: Preparation of2-((2R,6S)-2,6-dimethylmorpholino)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,(2R,6S)-2,6-dimethyl-4-(6-nitro-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine(190 mg, 0.503 mmol) was reduced with zinc dust (260 mg, 4.026 mmol) andammonium chloride (430 mg, 8.04 mmol) in THF/methanol/H₂O (3 mL/0.8mL/0.3 mL) to get the crude product (170 mg). LCMS: m/z=348.2 (M+1)⁺.

Step 5: Preparation ofN-(2-((2S,6R)-2,6-dimethylmorpholino)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride

Using the same reaction conditions as described in step 6 of example 1,2-((2R,6S)-2,6-dimethylmorpholino)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine(85 mg, 0.244 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (60 mg, 0.293 mmol)using EDCI.HCl (70 mg, 0.366 mmol), HOBt (50 mg, 0.366 mmol), DIPEA(0.94 mg, 0.732 mmol) in DMF (2 mL) to afford the crude product. Theresultant crude was purified by prep HPLC and treated with methanolicHCl to obtain the title compound (25 mg, 19.20%).

¹HNMR (CD₃OD, 300 MHz): δ 9.05 (s, 1H), 8.90-8.85 (d, 1H), 8.70 (s, 1H),8.60 (s, 1H), 8.58-8.45 (d, 1H), 4.06-3.97 (m, 2H), 3.85-3.79 (m, 2H),3.49 (s, 4H), 3.21-3.05 (t, 2H), 2.93 (s, 3H), 1.89 (s, 4H), 1.76 (s,2H), 1.29-1.21 (d, 6H). LCMS: 98.99%, m/z=534.3 (M+1)⁺. HPLC: 96.10%.

Example 542-(2-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example1,2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (productof step 6 of example 20) (70 mg, 0.219 mmol) was coupled with2-(2-methylpyridin-3-yl)oxazole-4-carboxylic acid (intermediate 8) (45mg, 0.219 mmol) using EDCI.HCl (63 mg, 0.329 mmol), HOBt (45 mg, 0.329mmol), DIPEA (71 mg, 0.548 mmol) in DMF (5 mL) to afford the crude titlecompound. The resultant crude was purified by prep HPLC to obtain thetitle compound (35 mg, 30%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.70 (s, 1H), 9.12 (s, 1H), 8.95 (s, 1H),8.82-8.74 (d, 1H), 8.68-8.62 (d, 1H), 7.83-7.72 (t, 1H), 3.74-3.72 (m,4H), 3.59-3.57 (m, 4H), 3.08 (s, 3H), 2.99 (s, 4H), 1.74 (s, 4H),1.65-1.52 (m, 2H). LCMS: 88.8%, m/z=506.2 (M+1)⁺. HPLC: 97.66%.

Example 552-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (productof step 6 of example 20) (70 mg, 0.219 mmol) was coupled with2-(2-hydroxypyridin-3-yl)oxazole-4-carboxylic acid (intermediate 9) (45mg, 0.219 mmol) using EDCI.HCl (63 mg, 0.329 mmol), HOBt (45 mg, 0.329mmol), DIPEA (71 mg, 0.548 mmol) in DMF (5 mL) to afford the crude titlecompound. The resultant crude was purified by prep HPLC to obtain thetitle compound (35 mg, 31.5%).

¹HNMR (DMSO-d₆, 400 MHz): δ 12.40 (s, 1H), 9.62 (s, 1H), 8.97 (s, 1H),8.89 (s, 1H), 8.23-8.21 (dd, 1H), 7.73-7.62 (m, 1H), 3.75-3.73 (m, 4H),3.58-3.56 (m, 4H), 2.99-2.96 (4H), 1.80 (s, 4H), 1.68-1.53 (m, 2H).LCMS: 100%, m/z=508.0 (M+1)⁺. HPLC: 96.21%.

Example 56N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methoxypyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of step 4of example 22) (70 mg, 0.220 mmol) was coupled with2-(2-methoxypyridin-4-yl)oxazole-4-carboxylic acid (intermediate 11) (53mg, 0.242 mmol) using EDCI.HCl (57 mg, 0.30 mmol), HOBt (41 mg, 0.30mmol), DIPEA (85 mg, 0.66 mmol) in DMF (5 mL) to afford the crudeproduct. The resultant crude was purified by prep HPLC to obtain thetitle compound (13 mg, 11%).

¹HNMR (CDCl₃, 300 MHz): δ 9.84 (s, 1H), 9.00 (s, 1H), 8.37 (s, 1H),8.34-8.33 (d, 1H), 7.52-7.50 (dd, 1H), 7.38 (s, 1H), 4.01 (s, 3H), 3.66(s, 4H), 3.12-3.09 (t, 4H), 1.88 (s, 4H), 1.69 (s, 8H).

LCMS: 100%, m/z=520.0 (M+1)⁺. HPLC: 94.16%.

Example 572-(6-methoxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (productof step 6 of example 20) (540 mg, 1.692 mmol) was coupled with2-(2-methoxypyridin-5-yl)oxazole-4-carboxylic acid (intermediate 7) (442mg, 2.031 mmol) using EDCI.HCl (484 mg, 25.39 mmol), HOBt (228 mg, 1.692mmol), DIPEA (1.3 g, 6.771 mmol) in DMF (5 mL) to afford the titlecompound (400 mg, 45%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.65 (s, 1H), 8.98-8.97 (d, 2H), 8.87 (s,1H), 8.35-8.30 (dd, 1H), 7.117.09 (d, 1H), 3.96 (s, 3H), 3.75-3.73 (m,4H), 3.59-3.58 (m, 4H), 3.10-3.00 (t, 4H), 1.82 (s, 4H), 1.20-1.10 (m,2H). LCMS: 95.26%, m/z=522.2 (M+1)⁺. HPLC: 95.37%.

Example 582-(2-methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (productof step 6 of example 20) (70 mg, 0.22 mmol) was coupled with2-(2-methoxypyridin-4-yl)oxazole-4-carboxylic acid (intermediate 11) (53mg, 0.242 mmol) using EDCI.HCl (63 mg, 0.33 mmol), HOBt (45 mg, 0.33mmol), DIPEA (85 mg, 0.66 mmol) in DMF (5 mL) to afford the titlecompound (25 mg, 21%).

¹HNMR (CD₃OD, 300 MHz): δ 8.99 (s, 1H), 8.59 (s, 1H), 8.35-8.30 (d, 1H),7.60-7.52 (d, 1H), 7.42 (s, 1H), 3.99 (s, 3H), 3.84-3.81 (t, 4H),3.67-3.64 (t, 4H), 3.11-3.08 (t, 4H), 1.90-1.85 (m, 4H), 1.80-1.70 (m,2H). LCMS: 88.28%, m/z=522.2 (M+1)⁺. HPLC: 91.56%.

Example 59(S)—N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of(S)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-ol

Using the same reaction conditions as described in step 2 of example 43,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (250 mg, 1.50 mmol) was substituted using(S)-piperidin-3-ol hydrochloride (137 mg, 0.9976 mmol) using sodiumcarbonate (265 mg, 2.4940 mmol) in DMF (2 mL) at 140° C. for 4 h toobtain the title compound (190 mg, 62.70%). LCMS: m/z=366.1 (M+1)⁺.

Step 2: Preparation of(S)-4-(5-(3-fluoropiperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

DAST (0.17 mL, 1.3013 mmol) was added to the cooled (−78° C.) solutionof (S)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-ol(190 mg, 0.5205 mmol) in DCM (5 mL). The reaction was quenched with icewater after stirring at −78° C. for 30 min. The compound was extractedwith DCM and purified by 60-120 silica gel column chromatography using2% methanol in DCM as eluent to obtain the title compound (100 mg,52.35%). LCMS: m/z=368.1 (M+1)⁺.

Step 3: Preparation of(S)-5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,(S)-4-(5-(3-fluoropiperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine(100 mg, 0.2724 mmol) was reduced with zinc dust (143 mg, 2.1798 mmol)and ammonium chloride (233 mg, 4.3596 mmol) in THF/methanol/H₂O (10 mL/2mL/1 mL) to get the crude product (100 mg). LCMS: m/z=338.1 (M+1)⁺.

Step 4: Preparation of(S)—N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,(S)-5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(100 mg, 0.2724 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (84 mg, 0.4087 mmol)using EDCI.HCl (79 mg, 0.4087 mmol), HOBt (56 mg, 0.4087 mmol), DIPEA(0.19 mL, 1.0899 mmol) in DMF (2 mL) to afford the crude product. Theresultant crude was purified by prep HPLC to obtain the title compound(26 mg, 18.30%).

¹HNMR (CDCl₃, 400 MHz): δ 9.94 (s, 1H), 9.09 (s, 1H), 8.69-8.68 (d, 1H),8.39 (s, 1H), 7.87 (s, 1H), 7.76-7.75 (d, 1H), 5.04-4.92 (m, 1H),3.84-3.82 (t, 4H), 3.71-3.68 (t, 4H), 3.45-3.36 (m, 2H), 3.15-3.02 (m,2H), 2.67 (s, 3H), 2.26-1.83 (m, 4H). LCMS: 97.00%, m/z=524.1 (M+1)⁺.

HPLC: 95.24%.

Example 602-(6-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (productof step 6 of example 20) (70 mg, 0.22 mmol) was coupled with2-(2-methylpyridin-5-yl)oxazole-4-carboxylic acid (intermediate 13) (54mg, 0.264 mmol) using EDCI.HCl (63 mg, 0.33 mmol), HOBt (40 mg, 0.33mmol), DIPEA (85 mg, 0.66 mmol) in DMF (5 mL) to afford the titlecompound (30 mg, 26%).

¹HNMR (CD₃OD, 400 MHz): δ 9.36 (s, 1H), 9.08-9.05 (dd, 1H), 8.85 (s,1H), 8.70 (s, 1H), 8.15-8.13 (d, 1H), 3.85-3.83 (t, 8H), 3.50-3.48 (m,4H), 2.88 (s, 3H), 1.85 (s, 4H), 1.80-1.70 (m, 2H).

LCMS: 98.51%, m/z=506.2 (M+1)⁺. HPLC: 94.43%.

Example 612-(3-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (productof step 6 of example 20) (80 mg, 0.25 mmol) was coupled with2-(3-methylpyridin-4-yl)oxazole-4-carboxylic acid (intermediate 12) (61mg, 0.3 mmol) using EDCI.HCl (72 mg, 0.376 mmol), HOBt (36 mg, 0.263mmol), DIPEA (97 mg, 0.75 mmol) in DMF (3.4 mL) to afford the titlecompound (29 mg, 23%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.70 (s, 1H), 9.09 (s, 1H), 8.99 (s, 1H),8.71 (s, 1H), 8.65-8.64 (d, 1H), 7.92-7.91 (d, 1H), 3.73-3.72 (m, 4H),3.65-3.55 (m, 4H), 2.96-2.95 (m, 4H), 2.78 (s, 3H), 1.76 (s, 4H), 1.59(s, 2H). LCMS: 99.47%, m/z=506.2 (M+1)⁺. HPLC: 98.79%.

Example 62(S)-6-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide

Step 1: Preparation of6-bromo-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (productof step 6 of example 20) (35 mg, 0.994 mmol) was coupled with6-bromopicolinic acid (301 mg, 1.49 mmol) using EDCI.HCl (285 mg, 1.49mmol), HOBt (141 mg, 1.04 mmol), DIPEA (384 mg, 2.98 mmol) in DMF (10mL) to afford the crude product. The resultant crude was purified by60-120 silica gel column chromatography using 1% methanol in DCM aseluent to obtain the title compound (220 mg, 40%). LCMS: m/z=503.0 (M)⁺.

Step 2: Preparation of tert-butyl(S)-(1-(6-((2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate

Using the same reaction conditions as described in step 2 of example 43,6-bromo-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide(70 mg, 0.139 mmol) was substituted with tert-butyl(S)-pyrrolidin-3-ylcarbamate (39 mg, 0.209 mmol) using sodium carbonate(59 mg, 0.556 mmol) in DMF (3 mL) at 140° C. for 4 h to obtain the titlecompound (40 mg, 46.5%).

Step 3: Preparation of(S)-6-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide

Using the same reaction conditions as described in step 8 of example 1,tert-butyl(S)-(1-(6-((2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(65 mg, 9.3655) was deprotected using TFA (2 mL) and DCM (8 mL) to getthe title compound (45 mg, 83.3%).

¹HNMR (CDCl₃, 400 MHz): δ 10.58 (s, 1H), 9.11 (s, 1H), 7.65-7.55 (m,2H), 6.57-6.55 (d, 1H), 3.87-3.77 (m, 6H), 3.68-3.3.63 (m, 5H),3.38-3.37 (m, 1H), 3.10-3.07 (t, 4H), 2.28-2.25 (m, 1H), 1.90-1.87 (m,1H), 1.77 (s, 4H), 1.57-1.55 (m, 3H). LCMS: 100%, m/z=509.1 (M+1)⁺.HPLC: 95.95%.

Example 63(S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazoo[4,5-b]pyridin-6-yl)picolinamide

Using the same reaction conditions as described in step 2 of example 43,6-bromo-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide(product of step 1 of example 63) (70 mg, 0.139 mmol) was substitutedwith (S)-pyrrolidin-3-ol (19 mg, 0.208 mmol) using sodium carbonate (59mg, 0.556 mmol) in DMF (3 mL) at 140° C. for 12 h to obtain the titlecompound (50 mg, 71.4%).

¹HNMR (DMSO-d₆, 400 MHz): δ 10.45 (s, 1H), 9.05 (s, 1H), 7.74-7.70 (t,1H), 7.38-7.37 (d, 1H), 6.75-6.74 (d, 1H), 5.06-5.05 (d, 1H), 4.44 (s,1H), 3.75-3.72 (m, 4H), 3.64-3.56 (m, 7H), 2.94-2.93 (d, 4H), 2.09-2.07(m, 1H), 1.98-1.95 (m, 1H), 1.72 (s, 4H), 1.57 (s, 2H).

LCMS: 94.83%, m/z=510.2 (M+1)⁺. HPLC: 95.34%.

Example 64(S)-6-(3-aminopyrrolidin-1-yl)-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide

Step 1: Preparation of6-bromo-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide

Using the same reaction conditions as described in step 6 of example 1,2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (product of step 4of example 22) (300 mg, 0.946 mmol) was coupled with 6-bromopicolinicacid (286 mg, 1.419 mmol) using EDCI.HCl (270 mg, 1.419 mmol), HOBt (191mg, 1.419 mmol), DIPEA (370 mg, 2.838 mmol) in DMF (5 mL) to afford thetitle compound (350 mg, 73.83%).

¹HNMR (CDCl₃, 300 MHz): δ 10.7 (s, 1H), 9.06 (s, 1H), 8.24-8.21 (d, 1H),7.80-7.75 (t, 1H), 7.67-7.64 (d, 1H), 3.65 (s, 4H), 3.12-3.08 (t, 4H),1.95-1.85 (m, 4H), 1.69 (s, 8H). LCMS: m/z=503.1 (M+2)⁺.

Step 2: Preparation of tert-butyl(S)-(1-(6-((2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate

Using the same reaction conditions as described in step 2 of example 43,6-bromo-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide(100 mg, 0.2 mmol) was substituted with tert-butyl(S)-pyrrolidin-3-ylcarbamate (56 mg, 0.3 mmol) using sodium carbonate(64 mg, 0.6 mmol) in DMF (2 mL) at 100° C. for 4 h to obtain the titlecompound (120 mg, 100%). LCMS: m/z=607.3 (M+1)⁺.

Step 3: Preparation of(S)-6-(3-aminopyrrolidin-1-yl)-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide

Using the same reaction conditions as described in step 8 of example 1,tert-butyl(S)-(1-(6-((2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)carbamoyl)pyridin-2-yl)pyrrolidin-3-yl)carbamate(120 mg, 0.197 mmol) was deprotected using TFA (1 mL) and DCM (1 mL) toafford the crude product. The resultant crude was purified by prep HPLCto obtain the title compound (65 mg, 65%).

¹HNMR (CDC₃, 300 MHz): δ 10.53 (s, 1H), 9.05 (s, 1H), 7.65-7.54 (m, 2H),6.55-6.53 (d, 1H), 3.84-3.73 (m, 3H), 3.64 (s, 6H), 3.50-3.35 (m, 1H),3.08-3.04 (t, 4H), 2.31-2.25 (m, 1H), 2.10-1.85 (m, 1H), 1.80-1.60 (m,11H). LCMS: 92.92%, m/z=507.2 (M+1)⁺. HPLC: 96.92%.

Example 65(S)—N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide

Using the same reaction conditions as described in step 2 of example 43,6-bromo-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide(product of step 1 of example 65) (70 mg, 0.14 mmol) was substitutedwith (S)-pyrrolidin-3-ol (20 mg, 0.209 mmol) using sodium carbonate (45mg, 0.42 mmol) in DMF (2 mL) at 100° C. for 4 h to obtain the titlecompound (60 mg, 84.5%).

¹HNMR (CDC₃, 400 MHz): δ 10.57 (s, 1H), 9.06 (s, 1H), 7.66-7.62 (t, 1H),7.59-7.57 (d, 1H), 6.58-6.56 (d, 1H), 4.68 (s, 1H), 3.79-3.74 (m, 4H),3.65 (s, 4H), 3.09-3.07 (m, 4H), 2.24-2.12 (m, 2H), 1.77-1.76 (m, 4H),1.69 (s, 6H), 1.61-1.56 (m, 3H). LCMS: 99.49%, m/z=508.2 (M+1)⁺.

HPLC: 99.62%.

Example 66(S)-2-(3-aminopyrrolidin-1-yl)-N-(2-morphlino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Step 1: Preparation of tert-butyl(S)-(1-(4-((2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)carbamoyl)oxazol-2-yl)pyrrolidin-3-yl)carbamate

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (productof step 6 of example 20) (100 mg, 0.3134 mmol), was coupled with(S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylicacid (intermediate 14) (140 mg, 0.4702 mmol) using EDCI.HCl (91 mg,0.4702 mmol), HOBt (64 mg, 0.4702 mmol), DIPEA (0.218 mL, 1.2539 mmol)in DMF (2 mL) to afford crude product. The resultant crude was purifiedby 60-120 silica gel column chromatography using 1% methanol in DCM aseluent to obtain the title compound (170 mg, 90.9%). LCMS: m/z=599.3(M+1)⁺. HPLC: 88.43%.

Step 2: Preparation of(S)-2-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 8 of example1,tert-butyl(S)-(1-(4-((2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)carbamoyl)oxazol-2-yl)pyrrolidin-3-yl)carbamate(170 mg, 0.2839 mmol) was deprotected using TFA (5 mL) and DCM (5 mL) toget the title compound (69 mg, 48.93%).

¹HNMR (CDCl₃, 400 MHz): δ 9.07 (s, 1H), 9.06 (s, 1H), 7.82 (s, 1H),3.82-3.68 (m, 11H), 3.30-3.28 (m, 1H), 3.15-3.03 (m, 4H), 2.30-2.20 (m,1H), 1.90-1.80 (m, 5H), 1.62-1.55 (m, 3H).

LCMS: 98.35%, m/z=499.2 (M+1)⁺. HPLC: 97.34%.

Example 67(S)—N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of tert-butyl(S)-(1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate

Using the same reaction conditions as described in step 1 of example 38,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (150 mg, 0.5 mmol) was substituted with tert-butyl(S)-pyrrolidin-3-ylcarbamate (93 mg, 0.5 mmol) using potassium carbonate(207 mg, 1.5 mmol) and DMF (5 mL) to afford the crude product. Theresultant crude was purified by 60-120 silica gel column chromatographyusing 1% methanol in DCM as eluent to obtain the title compound (195 mg,87%). LCMS: m/z=451.3 (M+1)⁺.

Step 2: Preparation of tert-butyl tert-butyl(S)-(1-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate

Using the same reaction conditions as described in step 2 of example 38,tert-butyl(S)-(1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate(194 mg, 0.431 mmol) was reduced with zinc dust (224 mg, 3.448 mmol) andammonium chloride (366 mg, 6.8977 mmol) in THF/methanol/H₂O (10 mL/2mL/1 mL) to get the title compound (171 mg, 94%). LCMS: m/z=421.2(M+1)⁺.

Step 3: Preparation of tert-butyl(S)-(1-(6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate

Using the same reaction conditions as described in step 6 of example 1,tert-butyl(S)-(1-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate(83 mg, 0.4047 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (170 mg, 0.4047 mmol)using EDCI.HCl (117 mg, 0.6155 mmol), HOBt (58 mg, 0.4293 mmol), DIPEA(209 mg, 1.624 mmol) in DMF (5 mL) to get the title compound (162 mg,66%). LCMS: m/z=607.2 (M+1)⁺.

HPLC: 95.47%.

Step 4: Preparation of(S)—N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 8 of example 1,tert-butyl(S)-(1-(6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-yl)carbamate(161 mg, 0.2656 mmol) was deprotected using methanolic HCl (5 mL) to getthe title compound (83 mg, 62%).

¹HNMR (CDCl₃, 300 MHz): δ 8.97 (s, 1H), 8.69-8.68 (d, 1H), 8.53 (s, 1H),8.40 (s, 1H), 7.79 (s, 1H), 7.73-7.71 (d, 1H), 3.84-3.80 (t, 4H),3.72-3.68 (m, 8H), 3.63-3.54 (m, 2H), 3.33-3.26 (m, 1H), 2.67 (s, 3H),2.28-2.24 (m, 1H), 1.82-1.78 (m, 1H). LCMS: 100%, m/z=507.1 (M+1)⁺.

HPLC: 97.85%.

Example 68(S)-2-(3-aminopyrrolidin-1-yl)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Step 1: Preparation of4-(5-cyclopropyl-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 7 of example1,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (500 mg, 1.666 mmol) was coupled with cyclopropylboronic acid (286 mg, 3.333 mmol) using potassium phosphate (882 mg,4.165 mmol) and Pd(OAc)₂ (57 mg, 0.254 mmol) and tricyclohexyl phosphine(70 mg, 0.254 mmol) in toluene:water (10/1 mL) to get the crude product.The resultant crude was purified by 60-120 silica gel columnchromatography using 30% ethyl acetate in hexane as eluent to obtain thetitle compound (400 mg, 80%). LCMS: m/z=306.9 (M+1)⁺.

Step 2: Preparation of5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example1,4-(5-cyclopropyl-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (400mg, 1.307 mmol) was reduced with zinc dust (680 mg, 10.457 mmol) andammonium chloride (1.13 g, 20.916 mmol) in THF (10 mL) to get the titlecompound (350 mg, 100%). LCMS: m/z=277.1 (M+1)⁺.

Step 3: Preparation of tert-butyl(S)-(1-(4-((5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)carbamoyl)oxazol-2-yl)pyrrolidin-3-yl)carbamate

Using the same reaction conditions as described in step 6 of example 1,5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-amine (100 mg, 0.362mmol), was coupled with(S)-2-(3-((tert-butoxycarbonyl)amino)pyrrolidin-1-yl)oxazole-4-carboxylicacid (intermediate 14) (129 mg, 0.434 mmol) using EDCI.HCl (102 mg, 0.54mmol), HOBt (73 mg, 0.54 mmol), DIPEA (0.280 mL, 2.16 mmol) in DMF (5mL) to afford the title compound (180 mg, 85.1%). LCMS: m/z=556.2(M+1)⁺.

Step 4: Preparation of(S)-2-(3-aminopyrrolidin-1-yl)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 8 of example 1,tert-butyl(S)-(1-(4-((5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)carbamoyl)oxazol-2-yl)pyrrolidin-3-yl)carbamate(180 mg, 0.324 mmol) was deprotected using TFA (1 mL) and DCM (0.5 mL)to get the crude product. The resultant crude was purified by prep HPLCto obtain the title compound (60 mg, 40.8%).

¹HNMR (CDCl₃, 300 MHz): δ 9.20 (s, 1H), 8.72 (s, 1H), 7.83 (s, 1H),3.83-3.56 (m, 12H), 3.28-3.25 (m, 1H), 2.22-2.18 (m, 1H), 2.10-2.03 (m,1H), 1.88-1.77 (m, 1H), 1.33-1.21 (m, 2H), 1.07-1.00 (m, 2H). LCMS:98.66%, m/z=456.2 (M+1)⁺. HPLC: 95.53%.

Example 69N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-cyclopropyl-2-morpholinothiazolo[4,5-h]pyridin-6-amine (product ofstep 2 of example 69) (100 mg, 0.362 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (110 mg, 0.54 mmol)using EDCI.HCl (102 mg, 0.54 mmol), HOBt (73 mg, 0.54 mmol), DIPEA (280mg, 2.16 mmol) in DMF (5 mL) to afford the title compound (45 mg,26.94%).

¹HNMR (CDCl₃, 400 MHz): δ 9.30 (s, 1H), 8.75-8.57 (m, 2H), 8.48 (s, 1H),7.85 (s, 1H), 7.75-7.72 (d, 1H), 3.90-3.80 (t, 4H), 3.78-3.70 (t, 4H),2.75 (s, 3H), 2.25-2.15 (m, 1H), 1.35-1.25 (m, 2H), 1.15-1.05 (m, 2H).LCMS: 98.37%, m/z=463.1 (M+1)⁺. HPLC: 97.74%.

Example 70(S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in example 45,2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (productof step 6 of example 20) (90 mg, 0.281 mmol), was coupled with(S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylicacid (intermediate 15) (105 mg, 0.3375 mmol) using EDCI.HCl (81 mg,0.4218 mmol), HOBt (57 mg, 0.4218 mmol), DIPEA (145 mg, 1.125 mmol) inDMF (2 mL) followed by deprotection using methanolic HCl (2 mL) to getthe title compound (63 mg, 84%).

¹HNMR (CDCl₃, 400 MHz): δ 9.75 (s, 1H), 9.07 (s, 1H), 7.85 (s, 1H), 4.67(bs, 1H), 3.843.59 (m, 12H), 3.12-3.09 (t, 4H), 2.30-2.10 (m, 2H), 1.85(s, 4H), 1.63-1.59 (m, 3H).

LCMS: 100%, m/z=500.3 (M+1)⁺. HPLC: 97.36%.

Example 71(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of(S)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol

Using the same reaction conditions as described in step 1 of example 38,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (150 mg, 0.5 mmol) was substituted with(S)-pyrrolidin-3-ol (43 mg, 0.5 mmol) using potassium carbonate (207 mg,1.5 mmol) and DMF (2 mL) to afford the title product (171 mg, 97%).LCMS: m/z=352.1 (M+1)⁺.

Step 2: Preparation of(S)-1-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol

Using the same reaction conditions as described in step 2 of example 38,(S)-1-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol(167 mg, 0.475 mmol) was reduced with zinc dust (247 mg, 3.806 mmol) andammonium chloride (403 mg, 7.6 mmol) in THF (10 mL) to get the titlecompound (147 mg, 96.7%). LCMS: m/z=322.1 (M+1)⁺.

Step 3: Preparation of(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,(S)-1-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol(146 mg, 0.6074 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (124 mg, 0.6074 mmol)using EDCI.HCl (175 mg, 0.911 mmol), HOBt (82 mg, 0.6074 mmol), DIPEA(354 mg, 2.429 mmol) in DMF (5 mL) to get the crude product. Theresultant crude was purified by prep HPLC to obtain the title compound(30 mg, 10%).

¹HNMR (CDCl₃, 400 MHz): δ 9.17 (s, 1H), 8.71-8.70 (d, 1H), 8.67 (s, 1H),8.43 (s, 1H), 7.83 (s, 1H), 7.76-7.75 (d, 1H), 4.60 (bs, 1H), 3.86-3.83(t, 4H), 3.76-3.68 (m, 6H), 3.60-3.54 (m, 3H), 2.69 (s, 3H), 2.26-2.24(m, 1H), 2.10-2.01 (m, 1H). LCMS: 100%, m/z=508.4 (M+1)⁺.

HPLC: 98.23%.

Example 72(S)—N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide

Step 1: Preparation of6-bromo-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)picolinamide

Using the same reaction conditions as described in example 45,5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-amine (product ofstep 2 of example 69) (220 mg, 0.797 mmol), was coupled with6-bromopicolinic acid (193 mg, 0.956 mmol) using EDCI.HCl (228 mg, 1.19mmol), HOBt (112 mg, 0.836 mmol), DIPEA (308 mg, 2.39 mmol) in DMF (10mL) to get the title compound (200 mg, 54.64%).

LCMS: m/z=460.0 (M+1)⁺.

Step 2: Preparation of(S)—N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide

Using the same reaction conditions as described in step 2 of example 43,6-bromo-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)picolinamide(100 mg, 0.217 mmol) was substituted with (S)-pyrrolidin-3-ol (40 mg,0.325 mmol) using sodium carbonate (92 mg, 0.868 mmol) in DMF (2 mL) at100° C. for 4 h to obtain the title compound (55 mg, 54.45%).

1HNMR (DMSO-d₆, 400 MHz): δ 10.41 (s, 1H), 8.60 (s, 1H), 7.71-7.67 (t,1H), 7.32-7.30 (d, 1H), 6.72-6.70 (d, 1H), 5.00-4.99 (d, 1H), 4.40 (s,1H), 3.73-3.70 (t, 4H), 3.58-3.51 (m, 7H), 2.19-2.16 (m, 1H), 2.18-2.00(m, 2H), 0.98-0.96 (m, 4H). LCMS: 100%, m/z=467.2 (M+1)⁺. HPLC: 95.50%.

Example 73(S)—N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in example 45,5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-amine (product ofstep 2 of example 69) (80 mg, 0.289 mmol), was coupled with(S)-2-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)oxazole-4-carboxylicacid (intermediate 15) (90 mg, 0.289 mmol) using EDCI.HCl (83 mg, 0.433mmol), HOBt (59 mg, 0.433 mmol), DIPEA (149 mg, 1.156 mmol) in DMF (5mL) followed by deprotection using methanolic HCl (5 mL) to get thetitle compound (40 mg, 44.4%).

¹HNMR (CDCl₃, 300 MHz): δ 9.19 (s, 1H), 8.71 (s, 1H), 7.84 (s, 1H), 4.65(s, 1H), 3.83-3.74 (t, 4H), 3.71-3.60 (m, 9H), 2.10-2.08 (m, 3H),1.21-1.19 (m, 2H), 1.06-1.02 (m, 2H). LCMS: 97.34%, m/z=457.4 (M+1).HPLC: 95.05%.

Example 74(S)—N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)picolinamide

Step 1: Preparation ofN-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide

Using the same reaction conditions as described in step 7 of example 1,6-bromo-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)picolinamide(product of step 1 of example 73) (100 mg, 0.217 mmol) was coupled with1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(79 mg, 0.282 mmol) using sodium carbonate (69 mg, 0.651 mmol) andPd(PPh₃)₂Cl₂ (8 mg, 0.108 mmol) in 1,2-dimethoxyethane/water (5/1 mL) toget the crude product. The resultant crude was purified by 60-120 silicagel column chromatography using 30% ethyl acetate in hexane as eluent toobtain the title compound (100 mg, 86.9%). LCMS: m/z=531.7 (M+1)⁺.

Step 2: Preparation ofN-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamidehydrochloride

Using the same reaction conditions as described in step 8 of example 1,N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)picolinamide(100 mg, 0.188 mmol) was deprotected using methanolic HCl (8 mL) to getthe title compound (90 mg, 94.7%). LCMS: m/z=447.7 (M+1)⁺.

Step 3: Preparationof(S)—N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)picolinamide

Using the same reaction conditions as described in step 2 of example 43,N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamidehydrochloride (90 mg, 0.201 mmol) was substituted with(S)-2-methyloxirane (24 mg, 0.402 mmol) using sodium carbonate (107 mg,1.00 mmol) in DMF (2 mL) at 140° C. for 4 h to obtain the crude product.The resultant crude was purified by prep HPLC to obtain the titlecompound (35 mg, 34.6%).

¹HNMR (DMSO-d₆, 400 MHz): δ 10.8 (s, 1H), 8.61 (s, 1H), 8.31-8.30 (d,2H), 8.00-7.98 (m, 1H), 7.93-7.89 (m, 2H), 5.02-5.01 (d, 1H), 4.05-4.02(m, 3H), 3.75 (s, 4H), 3.61 (s, 4H) 2.33-2.23 (m, 1H), 1.08-1.07 (d,3H), 0.99-0.95 (m, 4H). LCMS: m/z=505.7 (M+1)⁺. HPLC: 98.67%.

Example 75(S)—N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

Step 1: Preparation ofN-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamidehydrochloride

Using the same reaction conditions as described in example 45,6-bromo-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)picolinamide(product of step 1 of example 73) (100 mg, 0.362 mmol) was coupled with2-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)oxazole-4-carboxylicacid (intermediate 16) (95 mg, 0.362 mmol) using EDCI.HCl (103 mg, 0.543mmol), HOBt (73 mg, 0.543 mmol), DIPEA (187 mg, 1.448 mmol) in DMF (5mL) followed by deprotection using methanol/methanolic HCl (1/5 mL) toget the title compound (145 mg, 85.1%). LCMS: m/z=437.7 (M+1)⁺.

Step 2: Preparationof(S)—N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 2 of example 43,N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(1H-pyrazol-4-yl)oxazole-4-carboxamidehydrochloride (145 mg, 0.306 mmol) was substituted with(S)-2-methyloxirane (35 mg, 0.613 mmol) using sodium carbonate (162 mg,1.53 mmol) in DMF (2 mL) at 100° C. for 14 h to obtain the crudeproduct. The resultant crude was purified by prep HPLC to obtain thetitle compound (50 mg, 21.2%).

¹HNMR (CDCl₃, 400 MHz): δ 9.18 (s, 1H), 8.70 (s, 1H), 8.25 (s, 1H),8.05-8.03 (d, 2H), 4.28-4.25 (d, 3H), 3.83-3.81 (m, 4H), 3.70-3.69 (m,4H), 2.22-2.15 (m, 2H), 1.28-1.27 (m, 4H) 1.11-1.09 (d, 2H). LCMS:98.69%, m/z=496.2 (M+1)⁺. HPLC: 97.79%.

Example 76N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

Step 1: Preparation of1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol

Using the same reaction conditions as described in step 1 of example 38,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (125 mg, 0.4166 mmol) was substituted withpyrrolidin-3-ol hydrochloride (54 mg, 0.437 mmol) using potassiumcarbonate (230 mg, 1.666 mmol) and DMF (5 mL) to afford the titleproduct (102 mg, 70%).

LCMS: m/z=351.8 (M+1)⁺.

Step 2: Preparation of4-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 2 of example 41,1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol (100mg, 0.2857 mmol) was protected using TBDMS chloride (52 mg, 0.3428 mmol)and imidazole (43 mg, 0.712 mmol) in DMF (5 mL) at RT for 14 h to getthe crude product. The resultant crude was purified by 60-120 silica gelcolumn chromatography using 40% ethyl acetate in hexane as eluent toobtain the title compound (111 mg, 84%). LCMS: m/z=465.7 (M+1)⁺.

Step 3: Preparation of5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 2 of example 38,4-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine(110 mg, 0.2365 mmol) was reduced with zinc dust (123 mg, 1.8923 mmol)and ammonium chloride (200 mg, 3.7816 mmol) in THF/methanol/H₂O (10 mL/2mL/1 mL) to get the title compound (101 mg, 99%). LCMS: m/z=436.2(M+1)⁺.

Step 4: Preparation ofN-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(60 mg, 0.2727 mmol), was coupled with2-(6-methoxypyridin-3-yl)oxazole-4-carboxylic acid (intermediate 7) (100mg, 0.2298 mmol) using EDCI.HCl (80 mg, 0.4108 mmol), HOBt (39 mg,0.2865 mmol), DIPEA (142 mg, 1.095 mmol) in DMF (5 mL) to get the titlecompound (103 mg, 70%). LCMS: m/z=637.6 (M+1)⁺.

Step 5: Preparation ofN-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

TBAF (0.3 mL) was added to the stirred solution ofN-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide(100 mg, 0.1569 mmol) in THF (5 mL) and stirred at RT for 1 hr. Thereaction mass was diluted with saturated ammonium chloride solution andthe solid was filtered and suck dried to get the crude product. Theresultant crude was purified by 60-120 silica gel column chromatographyusing 2% methanol in DCM as eluent to obtain the title compound (35 mg,43%).

¹HNMR (CDCl₃, 400 MHz): δ 9.17 (s, 1H), 8.88 (s, 1H), 8.69 (s, 1H), 8.33(s, 1H), 8.22-8.20 (d, 1H), 6.88-6.86 (d, 1H), 4.57 (s, 1H), 4.02 (s,3H), 3.84-3.53 (m, 9H) 2.50-2.49 (d, 1H), 2.31-2.21 (m, 2H), 2.09-2.01(m, 2H). LCMS: 100%, m/z=524.3 (M+1)⁺. HPLC: 97.99%.

Example 77(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

Step 1: Preparation of(S)-4-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 2 of example 41,(S)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol(product of step 1 of example 72) (100 mg, 0.2857 mmol) was protectedusing TBDMS chloride (52 mg, 0.3428 mmol) and imidazole (43 mg, 0.712mmol) in DMF (5 mL) at RT for 14 h to get the crude product. Theresultant crude was purified by 60-120 silica gel column chromatographyusing 40% ethyl acetate in hexane as eluent to obtain the title compound(113 mg, 85%). LCMS: m/z=465.7 (M+1)⁺.

Step 2: Preparation of(S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 2 of example 38,(S)-4-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine(110 mg, 0.2365 mmol) was reduced with zinc dust (123 mg, 1.8923 mmol)and ammonium chloride (200 mg, 3.7816 mmol) in THF/methanol/H₂O (20 mL/2mL/1 mL) to get the title compound (100 mg, 98%). LCMS: m/z=436.3(M+1)⁺.

Step 3: Preparation of(S)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,(S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(60 mg, 0.2727 mmol), was coupled with2-(6-methoxypyridin-3-yl)oxazole-4-carboxylic acid (intermediate 7) (100mg, 0.2298 mmol) using EDCI.HCl (80 mg, 0.4108 mmol), HOBt (39 mg,0.2865 mmol), DIPEA (142 mg, 1.095 mmol) in DMF (5 mL) to get the titlecompound (102 mg, 70%). LCMS: m/z=637.6 (M+1)⁺.

Step 4: Preparation of(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

TBAF (0.3 mL) was added to the stirred solution of(S)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide(100 mg, 0.1569 mmol) in THF (5 mL) and stirred at RT for 1 hr. Thereaction mass was diluted with saturated ammonium chloride solution andthe solid was filtered and suck dried to get the crude product. Theresultant crude was purified by 60-120 silica gel column chromatographyusing 2% methanol in DCM as eluent to obtain the title compound (15 mg,18%).

¹HNMR (CDCl₃, 400 MHz): δ 9.17 (s, 1H), 8.88 (s, 1H), 8.69 (s, 1H), 8.33(s, 1H), 8.22-8.20 (d, 1H), 6.88-6.86 (d, 1H), 4.57 (s, 1H), 4.02 (s,3H), 3.83-3.81 (m, 4H), 3.76-3.69 (m, 4H), 3.68-3.51 (m, 4H), 2.47-2.46(d, 1H), 2.27-2.21 (m, 1H), 2.04-2.02 (m, 1H). LCMS: 100%, m/z=524.1(M+1)⁺. HPLC: 99.55%.

Example 78(R)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

Step 1: Preparation of(R)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol

Using the same reaction conditions as described in step 1 of example 38,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (125 mg, 0.4166 mmol) was substituted with(R)-pyrrolidin-3-ol (38 mg, 0.437 mmol) using potassium carbonate (230mg, 1.666 mmol) and DMF (5 mL) to afford the title product (101 mg,70%). LCMS: m/z=351.8 (M+1)⁺.

Step 2: Preparation of(R)-4-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 2 of example 41,(R)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol(100 mg, 0.2857 mmol) was protected using TBDMS chloride (52 mg, 0.3428mmol) and imidazole (43 mg, 0.712 mmol) in DMF (5 mL) at RT for 14 h toget the crude product. The resultant crude was purified by 60-120 silicagel column chromatography using 40% ethyl acetate in hexane as eluent toobtain the title compound (115 mg, 85.5%). LCMS: m/z=465.7 (M+1)⁺.

Step 3: Preparation of(R)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 2 of example 38,(R)-4-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine(110 mg, 0.2365 mmol) was reduced with zinc dust (123 mg, 1.8923 mmol)and ammonium chloride (200 mg, 3.7816 mmol) in THF/methanol/H₂O (20 mL/2mL/1 mL) to get the title compound (100 mg, 98%). LCMS: m/z=436.5(M+1)⁺.

Step 4: Preparation of(R)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,(R)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(60 mg, 0.2727 mmol), was coupled with2-(6-methoxypyridin-3-yl)oxazole-4-carboxylic acid (intermediate 7) (100mg, 0.2298 mmol) using EDCI.HCl (79 mg, 0.4108 mmol), HOBt (39 mg,0.2865 mmol), DIPEA (141 mg, 1.095 mmol) in DMF (5 mL) to get the titlecompound (110 mg, 75%). LCMS: m/z=637.6 (M+1)⁺.

Step 5: Preparation of(R)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

TBAF (0.3 mL) was added to the stirred solution of(R)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide(100 mg, 0.1569 mmol) in THF (5 mL) and stirred at RT for 1 hr. Thereaction mass was diluted with saturated ammonium chloride solution andthe solid was filtered and suck dried to get the crude product. Theresultant crude was purified by 60-120 silica gel column chromatographyusing 2% methanol in DCM as eluent to obtain the title compound (45 mg,55%).

¹HNMR (CDCl₃, 400 MHz): δ 9.17 (s, 1H), 8.88 (s, 1H), 8.69 (s, 1H), 8.33(s, 1H), 8.22-8.20 (dd, 1H), 6.88-6.86 (d, 1H), 4.57 (s, 1H), 4.02 (s,3H), 3.84-3.81 (m, 4H), 3.76-3.63 (m, 4H), 3.61-3.48 (m, 4H), 2.50-2.49(d, 1H), 2.44-2.22 (m, 1H), 2.04-2.03 (m, 1H). LCMS: 100%, m/z=524.1(M+1)⁺. HPLC: 98.62%.

Example 79(S)—N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide

Step 1: Preparation of4-(5-(azetidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 1 of example 38,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (200 mg, 0.666 mmol) was substituted withazetidine (76 mg, 1.333 mmol) using sodium carbonate (283 mg, 2.664mmol) and DMF (5 mL) to afford the title product (150 mg, 71.4%). LCMS:m/z=322.1 (M+1)⁺.

Step 2: Preparation of5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 2 of example 38,4-(5-(azetidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (150mg, 0.465 mmol) was reduced with zinc dust (243 mg, 3.726 mmol) andammonium chloride (402 mg, 7.440 mmol) in THF/methanol/H₂O (10 mL/2 mL/1mL) to get the title compound (150 mg, crude). LCMS: m/z=292.1 (M+1)⁺.

Step 3: Preparation ofN-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-bromopicolinamide

Using the same reaction conditions as described in example 45,5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (80 mg,0.2373 mmol), was coupled with 6-bromopicolinic acid (83 mg, 0.410 mmol)using EDCI.HCl (80 mg, 0.41 mmol), HOBt (55 mg, 0.410 mmol), DIPEA (141mg, 1.092 mmol) in DMF (5 mL) to get the title compound (130 mg, 100%).LCMS: m/z=477.1 (M+2)⁺.

Step 4: Preparation of(S)—N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide

Using the same reaction conditions as described in step 2 of example 43,N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-bromopicolinamide(100 mg, 0.210 mmol) was substituted with (S)-pyrrolidin-3-olhydrochloride (40 mg, 0.315 mmol) using sodium carbonate (90 mg, 0.840mmol) in DMF (2 mL) at 100° C. for 14 h to obtain the title compound (35mg, 35%).

¹HNMR (CDCl₃, 300 MHz): δ 9.79 (s, 1H), 8.59 (s, 1H), 7.66-7.60 (m, 1H),7.55-7.53 (d, 1H), 6.59-6.56 (d, 1H), 4.71 (s, 1H), 4.26-4.12 (m, 4H),3.83-3.76 (m, 4H), 3.74-3.65 (m, 8H), 2.32-2.19 (m, 4H). LCMS: 97.98%,m/z=482.2 (M+1)⁺. HPLC: 97.38%.

Example 80N-(5-(3-hydroxyazetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)azetidin-3-ol

Using the same reaction conditions as described in step 1 of example 38,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (200 mg, 0.6666 mmol) was substituted withazetidin-3-ol hydrochloride (109 mg, 1.0 mmol) using sodium carbonate(212 mg, 3.0 mmol) and DMF (2 mL) at 80° C. for 1 h to afford the titleproduct (160 mg, 71.11%). LCMS: m/z=338.1 (M+1)⁺.

Step 2: Preparation of4-(5-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 2 of example 41,1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)azetidin-3-ol (160mg, 0.4742 mmol) was protected using TBDMS chloride (86 mg, 0.5691 mmol)and imidazole (113 mg, 1.658 mmol) and DAMP (64 mg, 0.5217 mmol) in DMF(5 mL) at RT for 1 h to get the crude product. The resultant crude waspurified by 60-120 silica gel column chromatography using 1% methanol inDCM as eluent to obtain the title compound (210 mg, 98.59%). LCMS:m/z=452.2 (M+1)⁺.

Step 3: Preparation of5-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 2 of example 38,4-(5-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine(210 mg, 0.4656 mmol) was reduced with zinc dust (244 mg, 3.725 mmol)and ammonium chloride (399 mg, 7.4501 mmol) in THF/methanol/H₂O (10 mL/2mL/1 mL) to get the title compound (180 mg, 91.83%). LCMS: m/z=422.2(M+1)⁺.

Step 4: Preparation ofN-(5-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(180 mg, 0.4275 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (131 mg, 0.6413 mmol)using EDCI.HCl (123 mg, 0.6413 mmol), HOBt (87 mg, 0.6413 mmol), DIPEA(0.297 mL, 1.7102 mmol) in DMF (2 mL) to get the title compound (150 mg,57.91%).

Step 5: Preparation ofN-(5-(3-hydroxyazetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

TBAF (1M in THF) (0.5 mL) was added to the stirred solution ofN-(5-(3-((tert-butyldimethylsilyl)oxy)azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide(150 mg, 0.2467 mmol) in THF (20 mL) and stirred at RT for 1 hr. Thereaction mass was diluted with saturated ammonium chloride solution andthe solid was filtered and dried to get the crude product. The resultantcrude was purified by 60-120 silica gel column chromatography using 2%methanol in DCM as eluent to obtain the title compound (35 mg, 28.92%).

¹HNMR (DMSO-d₆, 300 MHz): δ 9.71 (s, 1H), 8.96 (s, 1H), 8.68-8.66 (d,1H), 7.90 (s, 1H), 7.85 (s, 1H), 7.77-7.75 (d, 1H), 5.51-5.49 (d, 1H),4.48-4.42 (m, 1H), 4.19-4.14 (t, 2H), 3.76-3.70 (m, 6H), 3.56-3.54 (m,4H), 2.57 (s, 3H). LCMS: 100%, m/z=494.1 (M+1)⁺. HPLC: 98.83%.

Example 81(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide

Step 1: Preparation of(S)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide

Using the same reaction conditions as described in step 6 of example 1,(S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(product of step 2 of compound 78) (90 mg, 0.206 mmol), was coupled with5-(2-methylpyridin-4-yl)thiophene-2-carboxylic acid (intermediate 17)(54 mg, 0.248 mmol) using EDCI.HCl (59 mg, 0.309 mmol), HOBt (42 mg,0.309 mmol), DIPEA (106 mg, 0.824 mmol) in DMF (5 mL) to get the titlecompound (120 mg, crude). LCMS: m/z=637.2 (M+1)⁺.

Step 2: Preparation of(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide

Using the same reaction conditions as described in step 8 of example 1(S)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide(120 mg, 0.188 mmol) was deprotected using methanolic HCl/methanol (5/1mL) to get the crude product. This was then purified by prep HPLC to getthe title compound (45 mg, 45.4%).

¹HNMR (CDCl₃, 400 MHz): δ 8.66 (s, 1H), 8.54-8.53 (d, 1H), 8.38 (s, 1H),7.70-7.69 (d, 1H), 7.489-7.480 (d, 1H), 7.38 (s, 1H), 7.34-7.32 (s, 1H),4.59 (s, 1H), 3.83-3.81 (m, 4H), 3.69-3.67 (m, 4H), 3.64-3.61 (m, 1H),3.53-3.50 (m, 3H), 2.62 (s, 3H), 229-2.19 (m, 1H), 2.18-1.90 (m, 1H).

LCMS: 99.27%, m/z=523.1 (M+1)⁺. HPLC: 96.58%.

Example 82(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

Step 1: Preparation of(S)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

Using the same reaction conditions as described in step 6 of example 1,(S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(product of step 2 of compound 78) (90 mg, 0.206 mmol), was coupled with5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (intermediate 18) (50mg, 0.248 mmol) using EDCI.HCl (59 mg, 0.309 mmol), HOBt (42 mg, 0.309mmol), DIPEA (106 mg, 0.824 mmol) in DMF (5 mL) to get the titlecompound (130 mg, crude).

Step 2: Preparation of(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

Using the same reaction conditions as described in step 8 of example 1(S)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide(130 mg, 0.209 mmol) was deprotected using methanolic HCl/methanol (5/1mL) to get the crude product. This was then purified by prep HPLC to getthe title compound (50 mg, 47.16%).

¹HNMR (CDCl₃, 300 MHz): δ 8.72 (s, 2H), 8.57-8.55 (d, 1H), 7.51 (s, 1H),7.44-7.42 (d, 1H), 7.36-7.34 (d, 1H), 7.00-6.99 (d, 1H), 4.62 (s, 1H),3.84-3.75 (m, 4H), 3.75-3.65 (m, 6H), 3.55-3.43 (m, 2H), 2.63 (s, 3H),2.42-2.39 (m, 1H), 2.26-2.21 (m, 1H), 2.06-1.99 (m, 1H). LCMS: 97.85%,m/z=507.2 (M+1)⁺. HPLC: 99.02%.

Example 83(S)—N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of(S)-4-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 2 of example 41,(S)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-ol(product of step 1 of example 59) (210 mg, 0.575 mmol) was protectedusing TBDMS chloride (108 mg, 0.719 mmol) and imidazole (98 mg, 1.438mmol) and DMAP (88 mg, 0.719 mmol) in DMF (5 mL) at RT for 14 h to getthe crude product. The resultant crude was purified by 60-120 silica gelcolumn chromatography using 1% methanol in DCM as eluent to obtain thetitle compound (177 mg, 64%). LCMS: m/z=480.3 (M+1)⁺.

Step 2: Preparation of(S)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 2 of example 38,(S)-4-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine(175 mg, 0.3645 mmol) was reduced with zinc dust (190 mg, 2.916 mmol)and ammonium chloride (312 mg, 5.833 mmol) in THF/methanol/water(20/10/5 mL) to get the title compound (162 mg, 98.7%).

LCMS: m/z=450.2 (M+1)⁺.

Step 3: Preparation of(S)—N-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,(S)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(160 mg, 0.355 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (91 mg, 0.444 mmol)using HATU (202 mg, 0.532 mmol) and DIPEA (183 mg, 1.42 mmol) in DMF (5mL) to get the title compound (198 mg, 88%). LCMS: m/z=634.3 (M−1)⁺.

Step 4: Preparation of(S)—N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 8 of example 1(S)—N-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide(197 mg, 0.3102 mmol) was deprotected using methanolic HCl/methanol (5/5mL) to get the title compound (138 mg, 85.7%).

¹HNMR (CDCl₃, 300 MHz): δ 9.78 (s, 1H), 9.05 (s, 1H), 8.71-8.69 (d, 1H),8.41 (s, 1H), 7.86 (s, 1H), 7.77-7.75 (d, 1H), 4.19-4.12 (m, 1H),3.84-3.81 (m, 4H), 3.71-3.67 (m, 4H), 3.33-3.32 (m, 1H), 3.24-3.13 (m,4H), 2.68 (s, 3H), 2.21-2.00 (m, 1H), 1.86-1.83 (m, 3H). LCMS: 98.40%,m/z=522.2 (M+1)⁺. HPLC: 98.37%.

Example 84N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-4-ol

Using the same reaction conditions as described in step 1 of example 38,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (200 mg, 0.6666 mmol) was substituted withpiperidine-4-ol (68 mg, 0.666 mmol) using potassium carbonate (311 mg,2.66 mmol) and DMF (5 mL) at RT for 14 h to afford the title product(211 mg, 87%).

LCMS: m/z=366.1 (M+1)⁺.

Step 2: Preparation of4-(5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 2 of example 41,1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-4-ol (210mg, 0.575 mmol) was protected using TBDMS chloride (108 mg, 0.7191 mmol)and imidazole (98 mg, 1.438 mmol) and DMAP (88 mg, 0.719 mmol) in DMF (5mL) at RT for 1 h to get the crude product. The resultant crude waspurified by 60-120 silica gel column chromatography using 1% methanol inDCM as eluent to obtain the title compound (216 mg, 78.2%). LCMS:m/z=480.2 (M+1)⁺.

Step 3: Preparation of5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 2 of example 38,4-(5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine(215 mg, 0.448 mmol) was reduced with zinc dust (233 mg, 3.583 mmol) andammonium chloride (387 mg, 7.16 mmol) in THF/methanol/H₂O (20 mL/5 mL/2mL) to get the title compound (161 mg, 80%).

LCMS: m/z=450.2 (M+1)⁺.

Step 4: Preparation ofN-(5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(160 mg, 0.355 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (91 mg, 0.444 mmol)using HATU (202 mg, 0.532 mmol) and DIPEA (0.183 mg, 1.42 mmol) in DMF(5 mL) to get the title compound (192 mg, 68%). LCMS: m/z=634.3 (M−1)⁺.

Step 5: Preparation ofN-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 8 of example 1N-(5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide(191 mg, 0.3 mmol) was deprotected using methanolic HCl/methanol (5/5mL) to get the title compound (130 mg, 83.3%).

¹HNMR (CDCl₃, 300 MHz): δ 9.87 (s, 1H), 9.05 (s, 1H), 8.70-8.68 (d, 1H),8.40 (s, 1H), 7.85 (s, 1H), 7.75-7.73 (d, 1H), 3.99-3.93 (m, 1H),3.84-3.81 (m, 4H), 3.70-3.67 (m, 4H), 3.35-3.30 (m, 2H), 3.11-3.08 (m,2H), 2.68 (s, 3H), 2.22-2.15 (m, 2H), 2.13-1.97 (m, 2H), 1.69-1.68 (m,1H).

LCMS: 94.22%, m/z=522.2 (M+1)⁺. HPLC: 97.51%.

Example 85(R)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of(R)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,(R)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(product of step 3 of example 79) (150 mg, 0.34 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (85 mg, 0.413 mmol)using HATU (196 mg, 0.517 mmol) and DIPEA (177 mg, 1.37 mmol) in DMF (8mL) to get the title compound (120 mg, 52.1%). LCMS: m/z=622.3 (M+1)⁺.

Step 2: Preparation of(R)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 8 of example 1,(R)—N-(5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinothiazolo[4,5b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide(120 mg, 0.1759 mmol) was deprotected using methanolic HCl/methanol (5/5mL) to get the title compound (77 mg, 65%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.99 (s, 1H), 8.96 (s, 1H), 8.69-8.68 (d,1H), 7.86 (s, 2H), 7.78-7.76 (d, 1H), 4.48 (s, 1H), 4.27 (s, 1H),3.74-3.72 (m, 4H), 3.64-3.52 (m, 6H), 2.59 (s, 3H), 2.09 (s, 1H),1.89-1.87 (m, 1H), 1.84-1.77 (m, 1H). LCMS: 97.25%, m/z=508.2 (M+1)⁺.HPLC: 95.18%.

Example 86N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

Step 1: Preparation ofN-(5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(product of step 3 of example 85) (150 mg, 0.334 mmol), was coupled with5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (intermediate 18) (68mg, 0.334 mmol) using HATU (190 mg, 0.501 mmol) and DIPEA (172 mg, 1.336mmol) in DMF (5 mL) to get the title compound (165 mg, 77.8%). LCMS:m/z=633.3 (M−1)⁺.

Step 2: Preparation ofN-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

Using the same reaction conditions as described in step 8 of example 1N-(5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide(160 mg, 0.252 mmol) was deprotected using methanolic HCl/metahnol (5/5mL) to get the title compound (107 mg, 81.6%).

¹HNMR (DMSO-d₆, 300 MHz): δ 9.61 (s, 1H), 8.58 (s, 1H), 8.55-8.53 (d,1H), 7.74 (s, 1H), 7.68-7.67 (d, 1H), 7.45-7.44 (d, 2H), 4.74 (s, 1H),3.74-3.73 (m, 4H), 3.66-3.58 (m, 5H), 2.90-2.83 (m, 2H), 2.56 (s, 3H),2.71-1.88 (m, 2H), 1.64-1.61 (m, 2H). LCMS: 99.09%, m/z=521.2 (M+1)⁺.

HPLC: 95.12%.

Example 87N-(5-(azetidin-1-yl)-2-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of5-(azetidin-1-yl)-6-nitro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 1 of example 38,5-chloro-6-nitro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridine (product ofstep 2 of example 22) (250 mg, 0.8389 mmol) was substituted withazetidine hydrochloride (117 mg, 1.2583 mmol) using sodium carbonate(267 mg, 2.5167 mmol) and DMF (5 mL) at RT overnight to afford the titleproduct (170 mg, 63.43%). LCMS: m/z=320.1 (M+1)⁺.

Step 2: Preparation of5-(azetidin-1-yl)-2-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 2 of example 38,5-(azetidin-1-yl)-6-nitro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridine (170mg, 0.5329 mmol) was reduced with zinc dust (228 mg, 4.2633 mmol) andammonium chloride (558 mg, 8.5266 mmol) in THF/methanol/H₂O (10 mL/2mL/1 mL) to get the title compound (140 mg, 90.9%). LCMS: m/z=290.1(M+1)⁺.

Step 3: Preparation ofN-(5-(azetidin-1-yl)-2-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(azetidin-1-yl)-2-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (140mg, 0.4844 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (119 mg, 0.5813 mmol)using HATU (294 mg, 0.6297 mmol) and DIPEA (0.338 mL, 1.9377 mmol) inDMF (3 mL) to get the title compound (96 mg, 41.73%).

¹HNMR (CDCl₃, 400 MHz): δ 8.70-8.69 (d, 1H), 8.55 (s, 1H), 8.38-8.36 (d,2H), 7.81 (s, 1H), 7.78-7.76 (d, 1H), 4.24-4.20 (t, 4H), 3.65 (s, 4H),2.69 (s, 3H), 2.40-2.33 (m, 2H), 1.69 (s, 6H).

LCMS: 100%, m/z=476.1 (M+1)⁺. HPLC: 97.70%.

Example 882-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Step 1: Preparation of6-nitro-2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 1 of example 38,5-chloro-6-nitro-2-(piperidin-1-yl)thiazolo[4,5-b]pyridine (product ofstep 2 of example 22) (250 mg, 0.8389 mmol) was substituted withpyrrolidine (90 mg, 1.2583 mmol) using sodium carbonate (178 mg, 1.6778mmol) and DMF (5 mL) at RT overnight to afford the title product (200mg, 71.42%). LCMS: m/z=334.1 (M+1)⁺.

Step 2: Preparation of2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 2 of example 38,6-nitro-2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridine(200 mg, 0.5998 mmol) was reduced with zinc dust (257 mg, 4.7988 mmol)and ammonium chloride (628 mg, 9.5977 mmol) in THF/methanol/H₂O (10 mL/2mL/1 mL) to get the title compound (140 mg, 76.92%). LCMS: m/z=304.1(M+1)⁺.

Step 3: Preparation of2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-amine(100 mg, 0.3300 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (81 mg, 0.3960 mmol)using HATU (163 mg, 0.4290 mmol) and DIPEA (0.23 mL, 1.3201 mmol) in DMF(3 mL) to get the title compound (59 mg, 36.64%).

¹HNMR (CDCl₃, 300 MHz): δ 8.95 (s, 1H), 8.69-8.68 (d, 1H), 8.48 (s, 1H),8.39 (s, 1H), 7.79 (s, 1H), 7.73-7.71 (d, 1H), 3.75-3.65 (m, 4H),3.55-3.49 (m, 4H), 2.67 (s, 3H), 1.99-1.94 (m, 4H), 1.69 (s, 6H). LCMS:98.26%, m/z=490.1 (M+1)⁺. HPLC: 97.87%.

Example 892-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Step 1: Preparation of4-(6-nitro-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 1 of example 38,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (200 mg, 0.666 mmol) was substituted withpyrrolidine (71 mg, 0.999 mmol) using potassium carbonate (275 mg, 1.998mmol) and DMF (5 mL) at RT overnight to afford the title product (200mg, 89.68%).

LCMS: m/z=336.0 (M+1)⁺.

Step 2: Preparation of2-morpholino-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 2 of example 38,4-(6-nitro-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine(200 mg, 0.597 mmol) was reduced with zinc dust (310 mg, 4.776 mmol) andammonium chloride (515 mg, 9.552 mmol) in THF/methanol/H₂O (10 mL/2 mL/1mL) to get the title compound (200 mg, crude). LCMS: m/z=306.1 (M+1)⁺.

Step 3:2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (100 mg,0.327 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (80 mg, 0.393 mmol)using HATU (186 mg, 0.490 mmol) and DIPEA (169 mg, 1.3081 mmol) in DMF(5 mL) to get the title compound (90 mg, 56.2%).

¹HNMR (CDCl₃, 300 MHz): δ 8.94 (s, 1H), 8.70-8.68 (d, 1H), 8.52 (s, 1H),8.40 (s, 1H), 7.79 (s, 1H), 7.73-7.71 (d, 1H), 3.83-3.80 (m, 4H),3.70-3.65 (m, 4H), 3.56-3.52 (m, 4H), 2.68 (s, 3H), 2.00-1.95 (m, 4H).LCMS: 100%, m/z=492.1 (M+1)⁺. HPLC: 97.29%.

Example 905-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)furan-2-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (productof step 6 of example 20) (150 mg, 0.468 mmol) was coupled with5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (intermediate 18) (114mg, 0.562 mmol) using HATU (267 mg, 0.702 mmol) and DIPEA (241 mg, 1.872mmol) in DMF (5 mL) to afford the title compound (60 mg, 25.4%).

¹HNMR (CDCl₃, 400 MHz): δ 9.08 (s, 1H), 8.58-8.57 (d, 1H), 7.58 (s, 1H),7.44-7.42 (d, 1H), 7.35-7.34 (d, 1H), 7.02-7.01 (d, 1H), 3.84-3.82 (m,4H), 3.71-3.68 (m, 4H), 3.13-3.10 (m, 4H), 2.64 (s, 3H), 1.99-1.86 (m,4H), 1.69 (s, 2H). LCMS: 100%, m/z=505.3 (M+1)⁺. HPLC: 95.52%.

Example 91N-(5-(azepan-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of4-(5-(azepan-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 1 of example 38,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (250 mg, 0.8333 mmol) was substituted with azepane(165 mg, 1.6666 mmol) using sodium carbonate (221 mg, 2.0833 mmol) andDMF (4 mL) at 80° C. for 2 h to afford the title product (200 mg,66.22%). LCMS: m/z=364.0 (M+1)⁺.

Step 2: Preparation of5-(azepan-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 2 of example 38,4-(5-(azepan-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (200mg, 0.550 mmol) was reduced with zinc dust (236 mg, 4.407 mmol) andammonium chloride (577 mg, 8.8154 mmol) in THF/methanol/H₂O (10 mL/2mL/2 mL) to get the title compound (100 mg, 52.93). LCMS: m/z=334.3(M+1)⁺.

Step 3: Preparation ofN-(5-(azepan-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(azepan-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (100 mg,0.300 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (74 mg, 0.360 mmol)using HATU (149 mg, 0.390 mmol) and DIPEA (0.21 mL, 1.2012 mmol) in DMF(5 mL) to get the title compound (84 mg, 53.84%).

¹HNMR (CDCl₃, 300 MHz): δ 9.85 (s, 1H), 9.07 (s, 1H), 8.69-8.67 (d, 1H),8.40 (s, 1H), 7.83 (s, 1H), 7.72-7.71 (d, 1H), 3.84-3.81 (m, 4H),3.70-3.67 (m, 4H), 3.39-3.32 (m, 4H), 2.67 (s, 3H), 1.93 (s, 8H). LCMS:89.19%, m/z=520.2 (M+1)⁺. HPLC: 95.29%.

Example 922-(2-aminopyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamidehydrochloride

Using the same reaction conditions as described in example 45,2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-amine (productof step 6 of example 20) (70 mg, 0.2191 mmol), was coupled with2-(2-((tert-butoxycarbonyl)amino)pyridin-4-yl)oxazole-4-carboxylic acid(intermediate 19) (74 mg, 0.2410 mmol) using HATU (108 mg, 0.2848 mmol)and DIPEA (0.153 mL, 0.8765 mmol) in DMF (2 mL) followed by deprotectionusing methanolic HCl/DCM (2/5 mL) to get the crude product. This wasthen purified by prep HPLC and treated with methanolic HCl to get thetitle compound (47 mg, 52.80%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.61 (s, 1H), 9.19 (s, 1H), 8.91 (s, 1H),8.49-8.41 (m, 2H), 8.21-8.19 (d, 1H), 7.53 (s, 1H), 7.30-7.28 (d, 1H),3.74-3.73 (m, 4H), (3.52-3.60 (m, 4H), 3.06-3.01 (m, 4H), 1.82-1.78 (m,4H), 1.64-1.61 (m, 2H). LCMS: 93.04%, m/z=507.2 (M+1)⁺. HPLC: 98.15%.

Example 93N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (product ofstep 2 of example 80) (100 mg, 0.344 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (105 mg, 0.517 mmol)using HATU (196 mg, 0.517 mmol) and DIPEA (177 mg, 1.376 mmol) in DMF (5mL) to afford title compound (40 mg, 25.0%).

¹HNMR (CDCl₃, 300 MHz): δ 8.71-8.69 (d, 1H), 8.57 (s, 1H), 8.42-8.39 (d,2H), 7.81 (s, 1H), 7.75-7.73 (d, 1H), 4.26-4.21 (t, 4H), 3.84-3.80 (m,4H), 3.69-3.66 (m, 4H), 2.69 (s, 3H), 2.39-2.34 (m, 2H). LCMS: 94.95%,m/z=478.1 (M+1)⁺. HPLC: 98.37%.

Example 94(R)—N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of(R)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-ol

Using the same reaction conditions as described in step 2 of example 43,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (400 mg, 1.333 mmol) was substituted using(R)-piperidin-3-ol hydrochloride (218 mg, 1.6 mmol) using potassiumcarbonate (552 mg, 4 mmol) in DMF (5 mL) at RT for 14 h to obtain thetitle compound (420 mg, 86.4%). LCMS: m/z=365.3 (M+1)⁺.

Step 2: Preparation of(R)-4-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 2 of example 41,(R)-1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-ol(420 mg, 0.903 mmol) was protected using TBDMS chloride (110 mg, 0.903mmol) and imidazole (92 mg, 1.354 mmol) and DMAP (204 mg, 1.354 mmol) inDMF/DCM (10/2 mL) at RT for 0.5 h to get the crude product. Theresultant crude was purified by 60-120 silica gel column chromatographyusing 2% methanol in DCM as eluent to obtain the title compound (520 mg,94.5%). LCMS: m/z=480.2 (M+1)⁺.

Step 3: Preparation of(R)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 2 of example 38,(R)-4-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine(520 mg, 0.898 mmol) was reduced with zinc dust (467 mg, 7.184 mmol) andammonium chloride (776 mg, 14.368 mmol) in THF/water (20/5 mL) to getthe title compound (500 mg crude). LCMS: m/z=450.0 (M+1)⁺.

Step 4: Preparation of(R)—N-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,(R)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(120 mg, 0.266 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (81 mg, 0.399 mmol)using HATU (152 mg, 0.399 mmol) and DIPEA (137 mg, 1.064 mmol) in DMF (3mL) to get the crude title compound (200 mg). LCMS: m/z=636.2 (M+1)⁺.

Step 5: Preparation of(R)—N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 5 of example 77,(R)—N-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide(200 mg, 0.314 mmol) was deprotected using TBAF/THF (2/5 mL) to get thecrude product. The resultant crude was purified by prep plate using 5%methanol in DCM as eluent to obtain the title compound (50 mg, 30.4%).

¹HNMR (CDCl₃, 400 MHz): δ 9.92 (s, 1H), 9.05 (s, 1H), 8.75 (s, 1H), 8.40(s, 1H), 7.87 (s, 1H), 7.69-7.67 (d, 1H), 4.15 (s, 1H), 3.84-3.82 (m,4H), 3.71-3.69 (m, 4H), 3.39-3.36 (m, 1H), 3.34-3.31 (m, 3H), 3.12-3.05(m, 1H), 2.68 (s, 3H), 2.20-2.10 (m, 1H), 1.90-1.60 (m, 3H). LCMS:97.74%, m/z=522.2 (M+1)⁺. HPLC: 98.12%.

Example 95(R)—N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

Using the same reaction conditions as described in example 45,(R)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(product of step 3 of example 95) (100 mg, 0.209 mmol), was coupled with5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (intermediate 18) (51mg, 0.250 mmol) using HATU (120 mg, 0.315 mmol) and DIPEA (108 mg, 0.840mmol) in DMF (5 mL) followed by deprotection using TBAF/THF (1/2 mL) toget the crude product. This was then purified by prep plate using 5%methanol in DCM as eluent to obtain the title compound (50 mg, 59.5%).

¹HNMR (CDCl₃, 300 MHz): δ 9.33 (s, 1H), 9.09 (s, 1H), 8.57-8.56 (d, 1H),7.59 (s, 1H), 7.45-7.44 (d, 1H), 7.37-7.35 (d, 1H), 7.00-6.99 (d, 1H),4.13 (s, 1H), 3.84-3.81 (m, 4H), 3.71-3.69 (m, 4H), 3.36-3.11 (m, 1H),3.19-3.10 (m, 3H), 2.64 (s, 3H), 2.39 (s, 1H) 2.17-2.11 (m, 1H),1.99-1.90 (m, 1H), 1.80-1.77 (m, 2H). LCMS: 93.43%, m/z=521.4 (M+1)⁺.HPLC: 95.34%.

Example 96(S)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide

Using the same reaction conditions as described in step 2 of example 43,N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide(example 21) (200 mg, 0.380 mmol) was substituted with(S)-2-methyloxirane (34 mg, 0.570 mmol) using sodium carbonate (201 mg,1.900 mmol) in DMF (5 mL) at 100° C. for 14 h to obtain the crudeproduct. The resultant crude was purified by prep plate using 5%methanol in DCM as eluent to obtain the title compound (50 mg, 24.5%).

¹HNMR (DMSO-d₆, 300 MHz): δ 10.59 (s, 1H), 9.03 (s, 1H), 8.42 (s, 1H),8.22 (s, 1H), 8.04-8.01 (m, 1H), 7.97-7.96 (m, 2H), 5.02 (s, 1H),4.06-4.04 (m, 3H), 3.72-3.70 (m, 4H), 3.58-3.55 (m, 4H), 3.02-2.89 (m,4H), 1.78-1.73 (m, 4H), 1.61-1.55 (m, 2H), 1.11-1.04 (m, 3H). LCMS:92.56%, m/z=549.3 (M+1)⁺. HPLC: 96.98%.

Example 97N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

Step 1: Preparation of4-(5-(4-fluoropiperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 2 of example 59,1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-4-ol(product of step 1 of example 85) (450 mg, 1.3846 mmol) was fluorinatedusing DAST (0.3 mL, 2.353 mmol) in DCM (10 mL) at −78° C. for 30 min.The resultant crude was purified by 60-120 silica gel columnchromatography using 50% ethyl acetate in hexane as eluent to obtain thecrude title compound (360 mg). LCMS: m/z=368.0 (M+1)⁺.

Step 2: Preparation of5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,4-(5-(4-fluoropiperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine(360 mg, 0.9809 mmol) was reduced with zinc dust (510 mg, 0.7847 mmol)and ammonium chloride (423 mg, 0.7847 mmol) in THF/methanol/H₂O (10 mL/2mL/1 mL) to get the crude product (240 mg). LCMS: m/z=338.3 (M+1)⁺.

Step 3: Preparation ofN-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(120 mg, 0.3560 mmol) was coupled with5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (intermediate 18) (86mg, 0.4272 mmol) using HATU (202 mg, 0.5341 mmol) and DIPEA (0.3 mL,1.424 mmol) in DMF (5 mL) to afford the crude product. The resultantcrude was purified by prep HPLC to obtain the title compound (75 mg,40%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.85 (s, 1H), 8.55-8.53 (d, 2H), 7.77 (s,1H), 7.69-7.68 (d, 1H), 7.46 (s, 2H), 4.95-4.79 (m, 1H), 3.75-3.73 (m,4H), 3.60-3.58 (m, 4H), 3.28-3.27 (m, 2H), 3.06-3.02 (m, 2H), 2.53 (s,3H), 2.06-2.02 (m, 2H), 1.92-1.90 (m, 2H). LCMS: 100%, m/z=523.2 (M+1)⁺.HPLC: 97.39%.

Example 98N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(product of step 2 of 98) (120 mg, 0.3560 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (87 mg, 0.4272 mmol)using HATU (202 mg, 0.5341 mmol) and DIPEA (183 mg, 1.024 mmol) in DMF(5 mL) to afford the crude product. The resultant crude was purified byprep HPLC to obtain the title compound (30 mg, 20%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.72 (s, 1H), 9.25 (s, 1H), 8.91-8.89 (m,2H), 8.24 (s, 1H), 8.14-8.12 (d, 1H), 5.08-4.91 (m, 1H), 3.7-3.73 (m,4H), 3.60-3.58 (m, 4H), 3.27-3.23 (m, 2H), 3.16 (s, 1H), 3.06-3.03 (m,2H), 2.76 (s, 2H), 2.25-2.15 (m, 2H), 2.10-2.02 (m, 2H). LCMS: 99.32%,m/z=524.0 (M+1)⁺. HPLC: 98.71%.

Example 99N-(5-(1-methyl-1H-pyrazol-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of4-(5-(1-methyl-1H-pyrazol-4-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 7 of example 1,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (200 mg, 0.66 mmol) was coupled with1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(200 mg, 0.99 mmol) using sodium iodide (200 mg, 1.33 mmol), potassiumcarbonate (220 mg, 1.99 mmol) and Pd(dppf)Cl₂ (48 mg, 0.066 mmol) in1,2-dimethoxyethane/water (0.5/0.2 mL) to get the title compound (150mg, %). LCMS: m/z=346.9 (M+1)⁺.

Step 2: Preparation of5-(1-methyl-1H-pyrazol-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,4-(5-(1-methyl-1H-pyrazol-4-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine(150 mg, 0.43 mmol) was reduced with zinc dust (220 mg, 3.4 mmol) andammonium chloride (360 mg, 6.9 mmol) in THF/methanol/H₂O (10 mL/2 mL/1mL) (2 mL) to get the crude product (100 mg). LCMS: m/z=317.3 (M+1)′.

Step 3: Preparation ofN-(5-(1-methyl-1H-pyrazol-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(1-methyl-1H-pyrazol-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(100 mg, 0.316 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (77 mg, 0.38 mmol)using HATU (156 mg, 0.41 mmol) and DIPEA (122 mg, 0.94 mmol) in DMF (5mL) to afford the title compound (40 mg, %).

¹HNMR (DMSO-d₆, 400 MHz): δ 10.1 (s, 1H), 9.05 (s, 1H), 8.71-8.70 (d,1H), 8.30 (s, 1H), 8.21 (s, 1H), 7.94 (s, 1H), 7.88 (s, 1H), 7.80-7.79(d, 1H), 3.87 (s, 3H), 3.82-3.76 (m, 4H), 3.69-3.64 (m, 4H), 2.60 (s,3H). LCMS: 97.70%, m/z=503.2 (M+1)⁺. HPLC: 96.20%.

Example 100N-(5-(3-fluorophenyl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of4-(5-(3-fluorophenyl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 7 of example 1,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (250 mg, 0.83 mmol) was coupled with 3-fluorophenyl boronic acid (173 mg, 1.25 mmol) using sodium iodide (375 mg, 2.5mmol), potassium carbonate (517 mg, 3.7 mmol) and Pd(dppf)Cl₂ (61 mg,0.1056 mmol) in 1,2-dimethoxyethane/water (0.5/0.2 mL) to get the titlecompound (200 mg, %). LCMS: m/z=361.2 (M+1)⁺.

Step 2: Preparation of5-(3-fluorophenyl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,4-(5-(3-fluorophenyl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (360mg, 0.9809 mmol) was reduced with zinc dust (510 mg, 0.7847 mmol) andammonium chloride (423 mg, 0.7847 mmol) in THF/methanol/H₂O (10 mL/2mL/1 mL) to get the crude product (240 mg). LCMS: m/z=330.9 (M+1)⁺.

Step 3: Preparation ofN-(5-(3-fluorophenyl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(3-fluorophenyl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (120 mg,0.36 mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylicacid (89 mg, 0.43 mmol) using HATU (180 mg, 0.47 mmol) and DIPEA (190mg, 1.45 mmol) in DMF (5 mL) to afford the title compound (50 mg).

¹HNMR (DMSO-d₆, 400 MHz): δ 10.10 (s, 1H), 8.94 (s, 1H), 8.68-8.67 (d,1H), 8.51 (s, 1H), 7.79 (s, 1H), 7.71-7.70 (d, 1H), 7.53-7.48 (m, 2H),7.27-7.24 (t, 1H), 3.77-3.75 (m, 4H), 3.70-3.66 (m, 4H), 2.54 (s, 3H).LCMS: 97.4%, m/z=517.0 (M+1)⁺. HPLC: 98.80%.

Example 101N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

Using the same reaction conditions as described in example 45,5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(product of step 3 of example 85) (200 mg, 0.445 mmol), was coupled with5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (intermediate 18) (135mg, 0.668 mmol) using HATU (253 mg, 0.668 mmol) and DIPEA (230 mg, 1.780mmol) in DMF (5 mL) followed by deprotection using methanol/methanolicHCl (1/5 mL) to get the crude product. This was then purified by prepHPLC to obtain the title compound (50 mg, 30.4%).

¹HNMR (CDCl₃, 400 MHz): δ 9.33 (s, 1H), 9.10 (s, 1H), 8.58-8.57 (d, 1H),7.60 (s, 1H), 7.46-7.45 (d, 1H), 7.37-7.36 (d, 1H), 7.01-7.00 (d, 1H),4.13 (s, 1H), 3.85-3.82 (m, 4H), 3.71-3.69 (m, 4H), 3.35-3.33 (m, 1H),3.20-3.10 (m, 3H), 2.65 (s, 3H), 2.35 (s, 1H), 2.14-2.12 (m, 1H),1.97-1.91 m, 1H), 1.79-1.77 (m, 2H). LCMS: 99.89%, m/z=521.20 (M+1)⁺.HPLC: 97.27%.

Example 102 N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

Using the same reaction conditions as described in step 6 of example 1,(S)-5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(product of step 4 of example 59) (200 mg, 0.593 mmol) was coupled with5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (intermediate 18) (180mg, 0.890 mmol) using HATU (338 mg, 0.890 mmol) and DIPEA (305 mg, 2.372mmol) in DMF (5 mL) to afford the crude product. The resultant crude waspurified by prep HPLC to obtain the title compound (40 mg, 12.9%).

¹HNMR (CDCl₃, 300 MHz): δ 9.51 (s, 1H), 9.14 (s, 1H), 8.56-8.54 (d, 1H),7.65 (s, 1H), 7.48-7.46 (d, 1H), 7.35-7.34 (d, 1H), 7.00-6.99 (d, 1H),5.05-4.90 (m, 1H), 3.85-3.81 (m, 4H), 3.71-3.68 (m, 4H), 3.49-3.44 (m,2H), 3.23-3.08 (m, 2H), 2.63 (s, 3H), 2.20-2.17 (m, 2H), 1.79-1.75 (m,2H).

LCMS: 98.09%, m/z=523.0 (M+1)⁺. HPLC: 99.18%.

Example 103(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in example 45,(S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine(product of step 2 of example 39) (130 mg, 0.3090 mmol), was coupledwith 2-(2-methoxypyridin-5-yl)oxazole-4-carboxylic acid (intermediate 7)(80 mg, 0.3636 mmol) using EDCI.HCl (105 mg, 0.5454 mmol), HOBt (52 mg,0.3817 mmol), DIPEA (188 mg, 1.454 mmol) in DMF (5 mL) to get thecoupled product followed by deprotection using 1M TBAF in THF/THF (0.3/5mL) to get the title compound (59 mg, 33%).

¹HNMR (CDCl₃, 300 MHz): δ 9.46 (s, 1H), 8.89-8.88 (d, 1H), 8.55 (s, 1H),8.32 (s, 1H), 8.23-8.19 (dd, 1H), 6.88-6.85 (dd, 1H), 4.55 (m, 1H), 4.02(s, 1H), 3.83-3.80 (m, 4H), 3.75-3.72 (m, 4H), 3.50-3.48 (m, 4H), 2.85(s, 1H), 2.26-2.22 (m, 1H), 2.05-2.01 (m, 1H). LCMS: 100%, m/z=508.1(M+1)⁺. HPLC: 98.32%.

Example 104N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol

Using the same reaction conditions as described in step 1 of example 38,5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of step 5of example 2) (250 mg, 0.880 mmol) was substituted with pyrrolidin-3-ol(108 mg, 0.880 mmol) using potassium carbonate (183 mg, 1.320 mmol) andDMF (5 mL) to afford the title product (210 mg, 72.41%). LCMS: m/z=335.8(M+1)⁺.

Step 2: Preparation5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 2 of example 41,1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)pyrrolidin-3-ol (150mg, 0.447 mmol) was protected using TBDMS chloride (102 mg, 0.6716mmol), imidazole (60 mg, 0.8955 mmol) and DMAP (10 mg, 0.089 mmol) inDMF (5 mL) at RT for 2 h to get the crude product. The resultant crudewas purified by 60-120 silica gel column chromatography using ethylacetate in hexane as eluent to obtain the title compound (160 mg, 80%).LCMS: m/z=449.8 (M+1)⁺.

Step 3: Preparation of5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine(160 mg, 0.3555 mmol) was reduced with zinc dust (0.1859 mg, 2.8444mmol) and ammonium chloride (304 mg, 5.688 mmol) in THF/methanol/H₂O (5mL/2 mL/1 mL) to get the title product (90 mg, 60.44%). LCMS: m/z=420.5(M+1)⁺.

Step 4: Preparation ofN-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in example 45,5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine(80 mg, 0.190 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (42 mg, 0.229 mmol)using EDCI.HCl (54 mg, 0.286 mmol), HOBt (38 mg, 0.2863 mmol), DIPEA (99mg, 0.7637 mmol) in DMF (3 mL) to get the coupled product followed bydeprotection using TBAF/THF (0.173/5 mL) to get the title compound (30mg, 53.57%).

¹HNMR (CDCl₃, 400 MHz): δ 9.46 (s, 1H), 8.69-8.68 (d, 1H), 8.52 (s, 1H),8.40 (s, 1H), 7.81 (s, 1H), 7.74-7.70 (d, 1H), 4.57 (s, 1H), 3.82-3.81(m, 4H), 3.75-3.74 (m, 4H), 3.61-3.59 (m, 1H), 3.57-3.46 (m, 1H),3.42-3.33 (m, 1H), 2.80-2.78 (d, 1H), 2.68 (s, 1H), 2.27-2.24 (m, 2H),2.05-2.02 (m, 2H), 1.03-0.99 (m, 1H). LCMS: 100%, m/z=492.1 (M+1)⁺.HPLC: 98.80%.

Example 105(R)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step example 45,(R)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine(product of step 3 of example 41) (57 mg, 0.1357 mmol), was coupled with2-(2-methoxypyridin-5-yl)oxazole-4-carboxylic acid (intermediate 7) (35mg, 0.1628 mmol) using EDCI.HCl (38 mg, 0.2035 mmol), HOBt (27 mg,0.2035 mmol), DIPEA (70 mg, 0.542 mmol) in DMF (5 mL) to get the coupledproduct followed by deprotection using TBAF/THF (0.144/5 mL) to get thetitle compound (10 mg, 20.44%).

¹HNMR (CDCl₃, 400 MHz): δ 9.47 (s, 1H), 8.89 (s, 1H), 8.55 (s, 1H), 8.33(s, 1H), 8.22-8.20 (d, 1H), 6.88-6.86 (d, 1H), 4.56-4.45 (m, 1H), 4.02(s, 3H), 3.82-3.81 (m, 4H), 3.75-3.74 (m, 4H), 3.65-3.47 (m, 3H),2.35-2.26 (m, 2H), 2.20-2.01 (m, 2H). LCMS: 94.67%, m/z=507.7 (M+1)⁺.HPLC: 97.15%.

Example 106N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine(product of step 3 of example 105) (90 mg, 0.2142 mmol), was coupledwith 2-(2-methoxypyridin-5-yl)oxazole-4-carboxylic acid (intermediate 7)(56 mg, 0.2571 mmol) using EDCI.HCl (62 mg, 0.3214 mmol), HOBt (43 mg,0.3214 mmol), DIPEA (110 mg, 0.8571 mmol) in DMF (3 mL) to get thecoupled product followed by deprotection using TBAF/THF (0.144/5 mL) toget the title compound (15 mg, 31.25%).

¹HNMR (CDCl₃, 400 MHz): δ 9.47 (s, 1H), 8.89 (s, 1H), 8.55 (s, 1H), 8.33(s, 1H), 8.22-8.20 (d, 1H), 6.88-6.86 (d, 1H), 4.56 (s, 1H), 4.02 (s,3H), 3.83-3.81 (m, 4H), 3.75-3.73 (m, 4H), 3.55-3.45 (m, 4H), 2.94-2.93(d, 1H), 2.30-2.25 (m, 1H), 2.09-2.01 (m, 1H). LCMS: 98.15%, m/z=507.7(M+1)⁺. HPLC: 98.95%.

Example 107(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

Using the same reaction conditions as described in example 45,(S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine(product of step 2 of example 39) (109 mg, 0.261 mmol), was coupled with5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (intermediate 18) (53mg, 0.261 mmol) using EDCI.HCl (75 mg, 0.3916 mmol), HOBt (37 mg, 0.2741mmol), DIPEA (135 mg, 1.046 mmol) in DMF (5 mL) to get the coupledproduct followed by deprotection using TBAF/THF (1/5 mL) to get thetitle compound (26 mg, 41.2%).

¹HNMR (CD₃OD, 400 MHz): δ 8.49-8.47 (d, 1H), 7.85 (s, 1H), 7.74-7.72 (d,1H), 7.70 (s, 1H), 7.40-7.39 (d, 1H), 7.33-7.32 (d, 1H), 4.45 (s, 1H),3.83-3.77 (m, 4H), 3.74-3.69 (m, 4H), 3.49-3.47 (m, 11H), 3.42-3.40 (m,1H), 3.21-3.16 (m, 1H), 2.61 (s, 3H), 2.09-2.07 (m, 1H), 1.89-1.86 (m,1H), 1.88-1.72 (m, 1H), 1.43-1.37 (m, 1H). LCMS: 100%, m/z=491.2 (M+1)⁺.HPLC: 97.91%.

Example 108(S)—N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide

Using the same reaction conditions as described in example 45,(S)-5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine(product of step 2 of example 39) (109 mg, 0.261 mmol), was coupled with5-(2-methylpyridin-4-yl)thiophene-2-carboxylic acid (intermediate 17)(57 mg, 0.261 mmol) using EDCI.HCl (75 mg, 0.3916 mmol), HOBt (37 mg,0.2741 mmol), DIPEA (135 mg, 1.046 mmol) in DMF (5 mL) to get thecoupled product followed by deprotection using TBAF/THF (1/5 mL) to getthe title compound (55 mg, 66%).

¹HNMR (CD₃OD, 400 MHz): δ 8.46-8.45 (d, 1H), 7.93-7.92 (d, 1H),7.76-7.75 (d, 1H), 7.65 (s, 1H), 7.61 (s, 1H), 7.57-7.56 (d, 1H), 4.43(s, 1H), 3.83-3.75 (m, 4H), 3.72-3.68 (m, 6H), 3.51-3.50 (m, 1H),3.42-3.36 (m, 1H), 2.60 (s, 3H), 2.07-2.05 (m, 1H), 1.93-1.92 (m, 1H).LCMS: 92.94%, m/z=507.2 (M+1)⁺. HPLC: 96.09%.

Example 109N-(5-(azetidin-1-yl)-2-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of 5-chloro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 3 of example 1,5-chloro-2-(methylthio)oxazolo[4,5-b]pyridine (product of step 3 ofexample 2) (3 g) was substituted using piperidine (8 mL) and THF (30 mL)to afford the title compound (3g, 90%).

LCMS: m/z=238.1 (M+1)⁺.

Step 2: Preparation of5-chloro-6-nitro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 4 of example 20,5-chloro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine (4 g, 168 mmol) wasnitrated using potassium nitrate (3.4 g, 337 mmol) and conc. sulphuricacid (20 mL) at RT for 3 h to afford the crude title compound (4g).

LCMS: m/z=283.0 (M+1)⁺.

Step 3: Preparation of5-(azetidin-1-yl)-6-nitro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 1 of example 38,5-chloro-6-nitro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine (400 mg, 1.418mmol) was substituted with azetidine hydrochloride (161 mg, 1.7021 mmol)using potassium carbonate (391 mg, 2.836 mmol) and THF (5 mL) to affordthe crude product (300 mg). LCMS: m/z=304.3 (M+1)⁺.

Step 4: Preparation of5-(azetidin-1-yl)-2-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,5-(azetidin-1-yl)-6-nitro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine (300mg, 0.990 mmol) was reduced with zinc dust (514 mg, 7.92 mmol) andammonium chloride (427 mg, 7.92 mmol) in THF/methanol/H₂O (10 mL/2 mL/1mL) to get the crude product (200 mg). LCMS: m/z=274.1 (M+1)⁺.

Step 5: Preparation ofN-(5-(azetidin-1-yl)-2-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(azetidin-1-yl)-2-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (100mg, 0.366 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (90 mg, 0.439 mmol)using HATU (208 mg, 0.549 mmol) and DIPEA (0.3 mL, 1.465 mmol) in DMF (5mL) to afford the title compound (60 mg, 36%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.81 (s, 1H), 8.97 (s, 1H), 8.69-8.68 (d,1H), 7.86 (s, 1H), 7.78-7.77 (d, 1H), 7.60 (s, 1H), 3.97-3.93 (t, 4H),3.65-3.60 (m, 4H), 2.59 (s, 3H), 2.20-2.17 (t, 2H), 1.62 (s, 6H). LCMS:97.60%, m/z=460.1 (M+1)⁺. HPLC: 96.38%.

Example 110N-(5-(azetidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of5-(azetidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 3 of example 1,5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of step 5of example 2) (200 mg, 0.701 mmol) was substituted with azetidine (81mg, 0.140 mmoland THF (5 mL) at RT for 2 h to afford the title compound(160 mg, 73.39%). LCMS: m/z=306.1 (M+1)⁺.

Step 2: Preparation of5-(azetidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,5-(azetidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (160 mg,0.5245 mmol) was reduced with zinc dust (274 mg, 4.196 mmol) andammonium chloride (448 mg, 8.393 mmol) in THF/methanol/H₂O (8 mL/2 mL/1mL) to get the title product (138 mg, 95.83%). LCMS: m/z=274.1 (M−1)⁺.

Step 3: Preparation ofN-(5-(azetidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(azetidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (150 mg,0.5454 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (166 mg, 0.818 mmol)using EDCI.HCl (156 mg, 0.818 mmol), HOBt (110 mg, 0.818 mmol) and DIPEA(282 mg, 2.1818 mmol) in DMF (5 mL) to afford the title compound (20 mg,8.0%).

¹HNMR (CDCl₃, 400 MHz): δ 8.70-8.69 (d, 1H), 8.62 (s, 1H), 8.39 (s, 1H),8.17 (s, 1H), 7.81 (s, 1H), 7.75-7.74 (d, 1H), 4.19-4.15 (t, 4H),3.82-3.81 (m, 4H), 3.74-3.73 (m, 4H), 2.69 (s, 3H), 2.37-2.33 (t, 2H).LCMS: 83.88%, m/z=462.1 (M+1)⁺. HPLC: 95.19%.

Example 1112-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Step 1: Preparation of6-nitro-2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 1 of example 38,5-chloro-6-nitro-2-(piperidin-1-yl)oxazolo[4,5-b]pyridine (product ofstep 2 of example 110) (400 mg, 1.418 mmol) was substituted withpyrrolidine (120 mg, 1.7021 mmol) in THF (10 mL) to afford the crudeproduct (300 mg). LCMS: m/z=318.2 (M+1)⁺.

Step 2: Preparation of2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,6-nitro-2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine(300 mg, 0.946 mmol) was reduced with zinc dust (492 mg, 7.57 mmol) andammonium chloride (409 mg, 7.57 mmol) in THF/methanol/H₂O (5 mL/2 mL/1mL) to get the crude product (200 mg). LCMS: m/z=288.1 (M+1)⁺.

Step 3: Preparation of2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (100mg, 0.348 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (80 mg, 0.418 mmol)using HATU (198 mg, 0.522 mmol) and DIPEA (0.3 mL, 1.393 mmol) in DMF (5mL) to afford the title compound (140 mg, 86%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.80 (s, 1H), 8.97 (s, 1H), 8.69-8.68 (d,1H), 7.85 (s, 1H), 7.77-7.76 (d, 1H), 7.66 (s, 1H), 3.61-3.60 (m, 4H),3.39-3.34 (m, 4H), 2.59 (s, 3H), 1.83 (s, 4H), 1.62 (s, 6H). LCMS:97.7%, m/z=474.2 (M+1)⁺. HPLC: 95.05%.

Example 1122-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Step 1: Preparation of2-morpholino-6-nitro-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 3 of example 1,5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of step 5of example 2) (200 mg, 0.701 mmol) was substituted with pyrrolidine (100mg, 0.7403 mmoland THF (5 mL) at RT for 2 h to afford the title compound(160 mg, 71.11%). LCMS: m/z=320.1 (M+1)⁺.

Step 2: Preparation of2-morpholino-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,2-morpholino-6-nitro-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridine (160 mg,0.5015 mmol) was reduced with zinc dust (262 mg, 0.4012 mmol) andammonium chloride (430 mg, 8.0250 mmol) in THF/methanol/H₂O (5 mL/2 mL/1mL) to get the title product (130 mg, 92.85%).

Step 3: Preparation of2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (148 mg,0.5172 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (158 mg, 0.7758 mmol)using EDCI.HCl (148 mg, 0.7758 mmol), HOBt (104 mg, 0.7758 mmol) andDIPEA (267 mg, 2.0689 mmol) in DMF (5 mL) to afford the title compound(80 mg, 33.05%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.82 (s, 1H), 8.96 (s, 1H), 8.69-8.68 (s,1H), 7.85 (s, 1H), 7.77-7.76 (d, 1H), 7.69 (s, 1H), 3.73-3.72 (m, 4H),3.69-3.68 (m, 4H), 3.62-3.59 (m, 4H), 2.59 (s, 3H), 1.84-1.81 (m, 4H).LCMS: 98.97%, m/z=476.2 (M+1)⁺. HPLC: 99.34%.

Example 1135-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)furan-2-carboxamide

Using the same reaction conditions as described in step 6 of example 1,2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-amine (product ofstep 2 of example 6) (70 mg, 0.3448 mmol), was coupled with5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (intermediate 18) usingHATU (196 mg, 0.5172 mmol), DIPEA (134 mg, 1.034 mmol) in DMF (5 mL) toafford the crude product. The resultant crude was purified by 60-120silica gel column chromatography using 2% methanol in DCM as eluent toobtain the title compound (46 mg, 29.8%).

¹HNMR (CDCl₃, 400 MHz): δ 9.85 (s, 1H), 8.79 (s, 1H), 8.58-8.56 (d, 1H),7.59 (s, 1H), 7.44-7.43 (d, 1H), 7.34-7.33 (d, 1H), 7.02-7.01 (d, 1H),3.84-3.81 (m, 4H), 3.76-3.74 (m, 4H), 3.07-3.04 (t, 4H), 2.64 (s, 3H),1.88-1.85 (m, 4H), 1.69 (s, 2H). LCMS: 100%, m/z=489.2 (M+1)⁺. HPLC:98.98%.

Example 114N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

Step 1: Preparation of1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)piperidin-4-ol

Using the same reaction conditions as described in step 3 of example 1,5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of step 5of example 2) (250 mg, 0.8802 mmol) was substituted with piperidin-4-ol(178 mg, 1.760 mmol) and THF (10 mL) at RT for 2 h to afford the titlecompound (300 mg, 97.71%). LCMS: m/z=350.1 (M+1)⁺.

Step 2: Preparation of5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 2 of example 41,1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)piperidin-4-ol (300mg, 0.859 mmol) was protected using TBDMS chloride (194 mg, 1.289 mmol)and imidazole (117 mg, 1.7191 mmol) and DMAP (21 mg, 1.719 mmol) in DMF(5 mL) at RT for 2 h to get the title compound (300 mg, 76%). LCMS:m/z=464.2 (M+1)⁺.

Step 3: Preparation of5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,5-(3-((tert-butyldimethylsilyl)oxy)pyrrolidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine(300 mg, 0.6479 mmol) was reduced with zinc dust (330 mg, 5.183 mmol)and ammonium chloride (554 mg, 10.367 mmol) in THF/methanol/H₂O (10 mL/2mL/1 mL) to get the title product (150 mg, 53.57%).

LCMS: m/z=434.2 (M+1)⁺.

Step 4: Preparation ofN-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

Using the same reaction conditions as described in example 45,5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine(150 mg, 0.346 mmol), was coupled with5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (intermediate 18) (84mg, 0.415 mmol) using HATU (171 mg, 0.4503 mmol) and DIPEA (178 mg,1.385 mmol) in DMF (3 mL) to get the coupled product followed bydeprotection using TBAF/THF (63 mg/5 mL) to get the title compound (40mg, 50%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.62 (s, 1H), 8.55-8.54 (d, 1H), 8.37 (s,1H), 7.74 (s, 1H), 7.68-7.67 (d, 1H), 7.48-7.45 (d, 2H), 4.80-4.79 (d,1H), 3.73-3.63 (m, 8H), 3.20-3.17 (m, 3H), 2.86-2.81 (t, 2H), 2.56 (s,3H), 1.91 (s, 2H), 1.67-1.65 (m, 2H). LCMS: 100%, m/z=505.2 (M+1)⁺.

HPLC: 96.82%.

Example 115(R)—N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

Step 1: Preparation of(R)-1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)piperidin-3-ol

Using the same reaction conditions as described in step 3 of example 1,5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of step 5of example 2) (250 mg, 0.8802 mmol) was substituted with(R)-piperidin-3-ol (121 mg, 1.88 mmol) and THF (10 mL) at RT for 2 h toafford the title compound (230 mg, 74.91%). LCMS: m/z=350.1 (M+1)⁺.

Step 2: Preparation of(R)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 2 of example 41,(R)-1-(2-morpholino-6-nitrooxazolo[4,5-h]pyridin-5-yl)piperidin-3-ol(230 mg. 0.659 mmol) was protected using TBDMS chloride (149 mg, 0.9885mmol) and imidazole (89 mg, 1.318 mmol) and DMAP (16 mg, 0.1318 mmol) inDMF (5 mL) at RT for 2 h to get the title compound (300 mg, 99.5%).

LCMS: m/z=464.2 (M+1)⁺.

Step 3: Preparation of(R)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,(R)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine(300 mg, 0.6479 mmol) was reduced with zinc dust (330 mg, 5.183 mmol)and ammonium chloride (554 mg, 10.367 mmol) in THF/methanol/H₂O (10 mL/2mL/1 mL) to get the title product (150 mg, 53.57%).

LCMS: m/z=434.2 (M+1)⁺.

Step 4: Preparation of(R)—N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide

Using the same reaction conditions as described in example 45,(R)-5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine(150 mg, 0.346 mmol), was coupled with5-(2-methylpyridin-4-yl)furan-2-carboxylic acid (intermediate 18) (84mg, 0.415 mmol) using HATU (171 mg, 0.4503 mmol) and DIPEA (178 mg,1.385 mmol) in DMF (3 mL) to get the coupled product followed bydeprotection using TBAF/THF (63 mg/5 mL) to get the title compound (32mg, 30.18%).

¹HNMR (DMSO-d₆, 400 MHz): δ +0.85 (s, 1H), 8.55-8.54 (d, 1H), 8.42 (s,1H), 7.81 (s, 1H), 7.70-7.68 (d, 1H), 7.48-7.46 (m, 2H), 4.92-4.91 (d,1H), 3.83 (s, 1H), 3.74-3.64 (m, 4H), 3.64-3.62 (m, 4H), 3.17-3.15 (m,1H), 3.02-2.99 (m, 1H), 2.83-2.79 (m, 1H), 2.73-2.70 (m, 1H), 2.55 (s,3H), 1.90-1.84 (m, 2H), 1.66-1.64 (m, 1H), 1.45-1.43 (m, 1H). LCMS:98.47%, m/z=505.2 (M+1)⁺.

HPLC: 98.78%.

Example 116N-(5-(furan-3-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of5-(furan-3-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 7 of example 1,5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of step 5of example 2) (300 mg, 1.0563 mmol) was coupled with furan-3-boronicacid (177 mg, 1.5845 mmol) using sodium iodide (237 mg, 1.5843 mmol) andPd(dppf)Cl₂ (86 mg, 0.1056 mmol) in 1,2-dimethoxyethane/water (5/1 mL)to get the crude title compound (170 mg). LCMS: m/z=317.1 (M+1)⁺.

Step 2: Preparation of5-(furan-3-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (170 mg, 0.5379mmol) was reduced with zinc dust (281 mg, 4.303 mmol) and ammoniumchloride (460 mg, 8.607 mmol) in THF/methanol/H₂O (10 mL/2 mL/1 mL) toget the title product (130 mg, 43.33%).

Step 3: Preparation ofN-(5-(furan-3-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(furan-3-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (100 mg, 0.3496mmol) was coupled with 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid(106 mg, 0.5244 mmol) using HATU (172 mg, 0.4545 mmol) and DIPEA (180mg) in DMF (5 mL) to afford the title compound (70 mg, 42.42%).

¹HNMR (DMSO-d₆, 400 MHz): δ 10.19 (s, 1H), 9.02 (s, 1H), 8.71-8.69 (d,1H), 8.14 (s, 1H), 7.94-7.87 (d, 2H), 7.79-7.75 (m, 2H), 7.01 (s, 1H),3.76-3.65 (m, 8H), 2.60 (s, 3H). LCMS: 100%, m/z=473.1 (M+1)⁺. HPLC:95.76%.

Example 117N-(5-(3-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)piperidin-3-ol

Using the same reaction conditions as described in step 3 of example 1,5-chloro-2-morpholino-6-nitrooxazolo[4,5-b]pyridine (product of step 5of example 2) (300 mg, 1.056 mmol) was substituted with piperidin-3-ol(211 mg, 2.110 mmol) and THF (5 mL) at RT for 14 h to afford the titlecompound (298 mg, 81%). LCMS: m/z=350.3 (M+1)⁺.

Step 2: Preparation of5-(3-fluoropiperidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 2 of example 59,1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)piperidin-3-ol (270mg, 0.7736 mmol) was fluorinated using DAST (218 mg, 1.353 mmol) in DCM(20 mL) at −78° C. for 1 h to obtain the title compound (240 mg, 88.4%).

Step 3: Preparation of5-(3-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,5-(3-fluoropiperidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine(230 mg, 0.6552 mmol) was reduced with zinc dust (340 mg, 5.24 mmol) andammonium chloride (555 mg, 10.48 mmol) in THF/water (20/5 mL) to get thetitle compound (145 mg, 69%).

Step 4: Preparation ofN-(5-(3-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(3-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine(120 mg, 0.3738 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (95 mg, 0.4672 mmol)using HATU (213 mg, 0.5605 mmol) and DIPEA (193 mg) in DMF (5 mL) toafford the crude compound. This was then purified by prep TLC using 3.5%methanol in chloroform to obtain the title compound (81 mg, 34%).

¹HNMR (DMSO-d₆, 300 MHz): δ 9.86 (s, 1H), 9.05 (s, 1H), 8.70-8.68 (d,1H), 8.62 (s, 1H), 7.85 (s, 1H), 7.75-7.74 (d, 1H), 5.10-4.90 (d, 1H),3.73-3.70 (t, 4H), 3.62-3.61 (t, 4H), 3.26-3.10 (m, 2H), 2.80-2.90 (m,2H), 2.57 (s, 3H), 2.20-1.70 (m, 4H). LCMS: 100%, m/z=508.0 (M+1)⁺.

HPLC: 99.27%.

Example 118N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in example 45,5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine(product of step 3 of example 115) (140 mg, 0.3233 mmol), was coupledwith 2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (66 mg, 0.3233mmol) using HATU (185 mg, 0.4868 mmol) and DIPEA (167 mg, 1.295 mmol) inDMF (5 mL) to get the coupled product followed by deprotection usingmethanol/MeOH. HCl (5/5 mL) to get the title compound (127 mg, 88%).

¹HNMR (DMSO-d₆, 300 MHz): δ 9.90 (s, 1H), 9.00 (s, 1H), 8.66-8.64 (d,1H), 8.58 (s, 1H), 7.83 (s, 1H), 7.74-7.72 (d, 1H), 4.90 (s, 1H),3.71-3.70 (m, 5H), 3.61-3.59 (d, 4H), 3.12-3.08 (m, 2H), 2.85-2.78 (t,2H), 2.57 (s, 3H), 1.99-1.96 (m, 2H), 1.79-1.76 (m, 2H). LCMS: 100%,m/z=506.1 (M+1)⁺. HPLC: 98.00%.

Example 119N-(5-(4-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of5-(4-fluoropiperidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 2 of example 59,1-(2-morpholino-6-nitrooxazolo[4,5-b]pyridin-5-yl)piperidin-4-ol(product of step 1 of example 115) (200 mg, 0.5730 mmol) was fluorinatedusing DAST (161 mg, 1.002 mmol) in DCM (20 mL) at −78° C. for 1 h toobtain the title compound (191 mg, 95%). LCMS: m/z=352.1 (M+1)⁺.

Step 2: Preparation of5-(4-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,5-(4-fluoropiperidin-1-yl)-2-morpholino-6-nitrooxazolo[4,5-b]pyridine(190 mg, 0.5413 mmol) was reduced with zinc dust (281 mg, 4.33 mmol) andammonium chloride (460 mg, 8.66 mmol) in THF/water (20/5 mL) to get thetitle product (90 mg, 52%).

Step 3: Preparation ofN-(5-(4-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(4-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-amine (85mg, 0.2647 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (67 mg, 0.328 mmol)using HATU (149 mg, 0.394 mmol) and DIPEA (135 mg, 1.050 mmol) in DMF (5mL) to afford the crude compound. This was then purified by prep TLCusing 3.5% methanol in chloroform to obtain the title compound (81 mg,34%).

¹HNMR (CDCl₃, 300 MHz): δ 10.00 (s, 1H), 8.76 (s, 1H), 8.70-8.69 (d,1H), 8.39 (s, 1H), 7.82 (s, 1H), 7.71-7.69 (dd, 1H), 5.00-4.70 (m, 1H),3.84-3.81 (t, 4H), 3.76-3.73 (t, 4H), 3.29-3.21 (m, 2H), 3.10-3.05 (m,2H), 2.67 (s, 3H), 2.27-2.18 (m, 4H). LCMS: 100%, m/z=508.3 (M+1)⁺.

HPLC: 90.17%.

Example 120(S)—N-(5-(3-aminopiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride

Step 1: Preparation of tert-butyl(S)-(1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-yl)carbamate

Using the same reaction conditions as described in step 1 of example 38,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (200 mg, 0.66 mol) was substituted with tert-butyl(S)-piperidin-3-ylcarbamate (199 mg, 0.99 mmol) using potassiumcarbonate (276 mg, 1.99 mmol) and THF (10 mL) to afford the crudeproduct which was taken as such for next step.

Step 2: Preparation of tert-butyl(S)-(1-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)piperidin-3-yl)carbamate

Using the same reaction conditions as described in step 5 of example 1,crude tert-butyl(S)-(1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-yl)carbamatewas reduced with zinc dust (338 mg, 5.1724 mmol) and ammonium chloride(553 mg, 10.344 mmol) in THF/methanol/H₂O (10 mL/2 mL/1 mL) to get thetitle compound (180 mg, 64.48%). LCMS: m/z=435.4 (M+1)⁺.

Step 3: Preparation of tert-butyl(S)-(1-(6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinothiazolo[4,5-b]pyridin-5-yl)piperidin-3-yl)carbamate

Using the similar reaction conditions as described in step 6 of example1, tert-butyl(S)-(1-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)piperidin-3-yl)carbamate(450 mg, 0.464 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (296 mg, 1.4547 mmol)using HATU (479 mg, 1.2607 mmol) and DIPEA (501 mg, 3.8793 mmol) in DMF(5 mL) to get the title compound (400 mg, 66.66%). LCMS: m/z=621.4(M+1)⁺.

Step 4: Preparation of(S)—N-(5-(3-aminopiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride

Using the same reaction conditions as described in step 8 of example 1,tert-butyl(S)-(1-(6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)-2-morpholinothiazolo[4,5-b]pyridin-5-yl)piperidin-3-yl)carbamate(400 mg, 0.6451 mmol) was deprotected using methanolic HCl/methanol (5/5mL) to get the title compound (100 mg, 94.33%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.71 (s, 1H), 9.24 (s, 1H), 8.85-8.83 (d,1H), 8.75 (s, 1H), 8.26 (s, 2H), 8.13 (s, 1H), 8.05-8.03 (d, 1H),3.75-3.73 (m, 5H), 3.42-3.39 (m, 4H), 3.16-3.04 (m, 3H), 2.90-2.80 (m,2H), 2.72 (s, 3H), 2.04-1.90 (m, 3H), 1.79-1.69 (m, 2H). LCMS: 86.06%,m/z=521.4 (M+1)⁺. HPLC: 98.61%.

Example 1212-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Step 1: Preparation of4-(6-nitro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 7 of example 1,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (250 mg, 0.833 mmol) was coupled with1-(tetrahydro-2H-pyran-2-yl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole(579 mg, 2.083 mmol) using sodium iodide (375 mg, 2.5 mmol), potassiumcarbonate (345 mg, 2.5 mmol) and Pd(dppf)Cl₂ (304 mg, 0.4166 mmol) in1,2-dimethoxyethane/water (5/1 mL) to get the title compound (150 mg,43.35%). LCMS: m/z=417.15 (M+1)⁺.

Step 2: Preparation of2-morpholino-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,4-(6-nitro-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-2-yl)morpholine(150 mg, 0.360 mmol) was reduced with zinc dust (188 mg, 2.8846 mmol)and ammonium chloride (308 mg, 5.769 mmol) in THF/water (5/1 mL) to getthe crude product (110 mg, 79.23%). LCMS: m/z=387.2 (M+1)⁺.

Step 3: Preparation of2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in example 45,2-morpholino-5-(1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-6-amine(130 mg, 0.336 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (103 mg, 0.505 mmol)using HATU (166 mg, 0.4378 mmol) and DIPEA (174 mg, 1.347 mmol) in DMF(5 mL) to get the coupled product followed by deprotection usingmethanol/MeOH HCl (2/5 mL) to get the title compound (75 mg, 67.56%).

¹HNMR (DMSO-d₆, 400 MHz): δ 13.0 (s, 1H), 10.18 (s, 1H), 9.02 (s, 1H),8.69-8.68 (d, 1H), 8.31 (s, 1H), 8.20-8.00 (bs, 2H), 7.87 (s, 1H),7.79-7.78 (d, 1H), 3.76-3.64 (m, 8H), 2.60 (s, 3H).

LCMS: 100%, m/z=489.3 (M+1)⁺. HPLC: 95.64%.

Example 122N-(5-(6-fluoropyridin-3-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of4-(5-(6-fluoropyridin-3-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 7 of example 1,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (200 mg, 0.666 mmol) was coupled with(6-fluoropyridin-3-yl)boronic acid (234 mg, 1.66 mmol) using sodiumiodide (299 mg, 1.99 mmol), potassium carbonate (276 mg, 1.99 mmol) andPd(dppf)Cl₂ (243 mg, 0.333 mmol) in 1,2-dimethoxyethane/water (5/1 mL)to get the title compound (152 mg, 63.33%).

Step 2: Preparation of5-(6-fluoropyridin-3-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,4-(5-(6-fluoropyridin-3-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine(152 mg, 0.4210 mmol) was reduced with zinc dust (220 mg, 3.368 mmol)and ammonium chloride (360 mg, 6.736 mmol) in THF/water (5/1 mL) to getthe crude product (150 mg). LCMS: m/z=331.9 (M+1)⁺.

Step 3: Preparation ofN-(5-(6-fluoropyridin-3-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the similar reaction conditions as described in step 6 of example1, crude5-(6-fluoropyridin-3-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (150mg, 0.4531 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (138 mg, 6.797 mmol)using HATU (223 mg, 0.589 mmol) and DIPEA (234 mg, 1.812 mmol) in DMF (5mL) to get the title compound (110 mg, 47%).

¹HNMR (DMSO-d₆, 400 MHz): δ 10.4 (s, 1H), 8.91 (s, 1H), 8.74 (s, 1H),8.68-8.66 (d, 1H), 8.589-8.582 (d, 1H), 8.427 (s, 1H), 8.00-7.98 (d,1H), 7.82 (s, 1H), 7.74-7.73 (d, 1H), 3.76-3.75 (t, 4H), 3.67-3.66 (t,4H), 2.58 (s, 3H). LCMS: 79.07%, m/z=518.3 (M+1)⁺. HPLC: 95.64%.

Example 123N-(5-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of8-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)-8-azabicyclo[3.2.1]octan-3-ol

Using the same reaction conditions as described in step 1 of example 38,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (300 mg, 1 mmol) was substituted with8-azabicyclo[3.2.1]octan-3-ol hydrochloride (195 mg, 1.2 mmol) usingpotassium carbonate (552 mg, 4 mmol) and DMF (5 mL) to afford the titleproduct (360 mg, 92.3%).

LCMS: m/z=392.1 (M+1)⁺.

Step 2: Preparation of8-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)-8-azabicyclo[3.2.1]octan-3-ol

Using the same reaction conditions as described in step 2 of example 38,8-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)-8-azabicyclo[3.2.1]octan-3-ol(350 mg, 0.8951 mmol) was reduced with zinc dust (468 mg, 7.161 mmol)and ammonium chloride (766 mg, 14.321 mmol) in THF/water (10/2 mL) toget the title compound (280 mg, 86.68%). LCMS: m/z=362.1 (M+1)⁺.

Step 3: Preparation ofN-(5-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,8-(6-amino-2-morpholinothiazolo[4,5-b]pyridin-5-yl)-8-azabicyclo[3.2.1]octan-3-ol(100 mg, 0.2770 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (85 mg, 0.4155 mmol)using HATU (136 mg, 0.3601 mmol) and DIPEA (143 mg, 1.108 mmol) in DMF(5 mL) to get the title compound (120 mg, 79.47%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.52 (s, 1H), 9.08 (s, 1H), 8.78 (s, 1H),8.71-8.70 (d, 1H), 7.81 (s, 1H), 7.73-7.72 (s, 1H), 4.568-4.563 (d, 1H),4.10 (s, 1H), 4.03 (s, 2H), 3.74-3.72 (t, 4H), 3.58-3.55 (m, 4H), 2.59(s, 3H), 2.42-2.39 (m, 2H), 2.20-2.18 (m, 2H), 1.94-1.93 (m, 2H),1.83-1.80 (m, 2H). LCMS: 100%, m/z=548.5 (M+1)′. HPLC: 95.67%.

Example 124N-(2-(3-hydroxypiperidin-1-yl)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of 6-bromo-5-chlorothiazolo[4,5-b]pyridine-2-thiol

Using the same reaction conditions as described in step 1 of example 1,3,5-dibromo-6-chloropyridin-2-amine (3 g, 10.489 mmol) was cyclisedusing potassium ethyl xanthate (3 g, 18.881 mmol) in DMF (50 mL) at 155°C. for 3 h to afford the title product (2.95 g, 100%). LCMS: m/z=280.8(M−1)⁺.

Step 2: Preparation of6-bromo-5-chloro-2-(methylthio)thiazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 2 of example 1,6-bromo-5-chlorothiazolo[4,5-b]pyridine-2-thiol (3 g, 10.676 mmol) wasmethylated using potassium carbonate (2.94 g, 21.352 mmol) and methyliodide (2.29 g, 16.014 mmol) in ethyl acetate (100 mL) to afford thetitle compound (3.16 g, 100%). LCMS: m/z=296.7 (M+1)⁺.

Step 3: Preparation of2-(3-(benzyloxy)piperidin-1-yl)-6-bromo-5-chlorothiazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 1 of example 38,6-bromo-5-chloro-2-(methylthio)thiazolo[4,5-b]pyridine (500 mg, 1.689mmol) was substituted with 3-(benzyloxy)piperidine hydrochloride (322mg, 1.689 mmol) using potassium carbonate (932 mg, 6.756 mmol) and THF(5 mL) at 85° C. for 14 h to afford the crude product. The crude productwas purified by using 60-120 silica-gel column chromatography andcompound was eluted using 30% ethyl acetate in hexane as eluent toafford the title compound (280 mg, 37.8%). LCMS: m/z=438.2 (M)⁺.

Step 4: Preparation of2-(3-(benzyloxy)piperidin-1-yl)-6-bromo-5-(piperidin-1-yl)thiazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 1 of example6,2-(3-(benzyloxy)piperidin-1-yl)-6-bromo-5-chlorothiazolo[4,5-b]pyridine(280 mg, 0.639 mmol) was substituted using piperidine (1 mL) in THF (1mL) 125° C. for 14 h to obtain the crude product (280 mg). LCMS:m/z=489.1 (M+2)⁺.

Step 5: Preparation ofN-(2-(3-(benzyloxy)piperidin-1-yl)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

To the solution of2-(3-(benzyloxy)piperidin-1-yl)-6-bromo-5-(piperidin-1-yl)thiazolo[4,5-b]pyridine(50 mg, 0.102 mmol), 2-(2-methylpyridin-4-yl)oxazole-4-carboxamide (31mg, 0.154 mmol) (intermediate 23) and potassium phosphate (65 mg, 0.306mmol) in 1,4-dioxane (4 mL) was added copper iodide (2 mg, 0.01 mmol)and trans-N1,N2-dimethylcyclohexane-1,2-diamine (5 mg, 0.030 mmol) andheated at 110° C. for 14 h. The solvent was distilled out and purifiedby 60-120 silica gel column chromatography using 5% methanol in DCM aseluent to obtain the title compound (40 mg, 64.5%). LCMS: m/z=610.3(M+1)⁺.

Step 6: Preparation ofN-(2-(3-hydroxypiperidin-1-yl)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the similar reaction conditions as described in step 8 of example1,N-(2-(3-(benzyloxy)piperidin-1-yl)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide(200 mg, 0.328 mmol) was deprotected using TFA (5 mL) and toluene (1 mL)at 110° C. for 14 h to afford the crude product. The resultant crude waspurified by prep HPLC to obtain the title compound (50 mg, 29.4%).

¹HNMR (CDCl₃, 300 MHz): δ 9.90 (s, 1H), 9.00 (s, 1H), 8.70-8.69 (d, 1H),8.39 (s, 1H), 7.83 (s, 1H), 7.74-7.25 (s, 1H), 4.05-3.94 (m, 2H),3.85-3.70 (m, 1H), 3.53-3.51 (m, 2H), 3.14-3.10 (t, 4H), 2.67 (s, 3H),1.92-1.58 (m, 11H). LCMS: 96.10%, m/z=520.4 (M+1)⁺. HPLC: 97.47%.

Example 1252-(2-acetamidopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in example 45,5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(product of step 3 of example 85) (155 mg, 0.3452 mmol), was coupledwith 2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylic acid (intermediate20) (106 mg, 0.4315 mmol) using HATU (197 mg, 0.5188 mmol) and DIPEA(179 mg, 1.3835 mmol) in DMF (5 mL) to get the crude compound followedby deprotection using TBAF/THF (1/10 mL) to get the title compound (42mg, 46%).

¹HNMR (CDCl₃, 300 MHz): δ 9.10 (s, 1H), 8.60 (s, 1H), 8.32-8.31 (d, 1H),7.42-7.41 (d, 1H), 7.33-7.32 (d, 1H), 7.07-7.06 (d, 1H), 3.18 (s, 4H),3.69-3.67 (m, 4H), 3.30-3.26 (m, 2H), 3.09-3.01 (t, 2H), 2.26 (s, 3H),2.19-2.16 (m, 2H), 2.00-1.87 (m, 4H). LCMS: 96.40%, m/z=564.4 (M+1)⁺.

HPLC: 96.95%.

Example 126N-(2-(3-hydroxypiperidin-1-yl)-5-(4-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of1-(2-(3-(benzyloxy)piperidin-1-yl)-6-bromothiazolo[4,5-b]pyridin-5-yl)piperidin-4-ol

Using the same reaction conditions as described in step 1 of example 38,2-(3-(benzyloxy)piperidin-1-yl)-6-bromo-5-(piperidin-1-yl)thiazolo[4,5-b]pyridine(product of step 3 of example 125) (200 mg, 0.456 mmol) was substitutedwith 4-hydroxypiperidine (56 mg, 0.547 mmol) using potassium carbonate(126 mg, 0.912 mmol) and DMF (5 mL) at 150° C. for 5 h to afford thecrude product (250 mg). LCMS: m/z=505.3 (M+2)⁺.

Step 2: Preparation of2-(3-(benzyloxy)piperidin-1-yl)-6-bromo-5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)thiazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 2 of example 41,1-(2-(3-(benzyloxy)piperidin-1-yl)-6-bromothiazolo[4,5-b]pyridin-5-yl)piperidin-4-ol(250 mg, 0.496 mmol) was protected using TBDMS chloride (149 mg, 0.992mmol), imidazole (50 mg, 0.744 mmol) and DMAP (60 mg, 0.496 mmol) in DMF(5 mL) at RT for 2 h to get the crude product (306 mg).

Step 3: Preparation ofN-(2-(3-(benzyloxy)piperidin-1-yl)-5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 5 of example125,2-(3-(benzyloxy)piperidin-1-yl)-6-bromo-5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)thiazolo[4,5-b]pyridine(306 mg, 0.495 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxamide (120 mg, 0.595 mmol)(intermediate 23) using potassium phosphate (314 mg, 1.485 mmol), copperiodide (10 mg, 0.049 mmol) andtrans-N1,N2-dimethylcyclohexane-1,2-diamine (21 mg, 0.148 mmol) in1,4-dioxane (5 mL) at 110° C. for 14 hand purified by 60-120 silica gelcolumn chromatography using 2% methanol in DCM as eluent to obtain thetitle compound (300 mg, 84.2%).

Step 4: Preparation ofN-(2-(3-(benzyloxy)piperidin-1-yl)-5-(4-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 8 of example1,N-(2-(3-(benzyloxy)piperidin-1-yl)-5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide(150 mg, 0.202 mmol) was deprotected using methanolic.HCl/methanol (l/1mL) to get the crude compound (120 mg). LCMS: m/z=626.4 (M+1)⁺.

Step 5: Preparation ofN-(2-(3-hydroxypiperidin-1-yl)-5-(4-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the similar reaction conditions as described in step 8 of example1,N-(2-(3-(benzyloxy)piperidin-1-yl)-5-(4-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide(120 mg, 0.191 mmol) was deprotected using TFA (5 mL) and toluene (1 mL)at 110° C. for 1 h to afford the crude product. The resultant crude waspurified by prep HPLC to obtain the title compound (40 mg, 39.2%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.76 (s, 1H), 9.08 (s, 1H), 8.91 (s, 1H),8.70-8.69 (d, 1H), 7.89 (s, 1H), 7.79-7.77 (d, 1H), 5.09-5.08 (d, 1H),4.90-4.89 (d, 1H), 3.88-3.86 (m, 1H), 3.73-3.62 (m, 3H), 3.21-3.11 (m,4H), 2.89-2.86 (t, 2H), 2.67 (s, 3H), 2.02-1.99 (m, 2H), 1.90-1.77 (m,4H), 1.53-1.23 (m, 2H). LCMS: 81.88%, m/z=536.3 (M+1)⁺. HPLC: 98.31%.

Example 1272-(2-acetamidopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Step 1: Preparation of1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-ol

Using the same reaction conditions as described in step 2 of example 43,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (500 mg, 1.66 mol) was substituted usingpiperidin-3-ol (202 mg, 1.99 mmol) using potassium carbonate (691 mg,4.99 mmol) in DMF (5 mL) at RT for 2 h to obtain the title compound (500mg, 83.33%). LCMS: m/z=366.2 (M+1)⁺.

Step 2: Preparation of4-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 2 of example 41,1-(2-morpholino-6-nitrothiazolo[4,5-b]pyridin-5-yl)piperidin-3-ol (300mg, 0.8219 mmol) was protected using TBDMS chloride (185 mg, 1.232 mmol)and imidazole (111 mg, 1.643 mmol) and DMAP (20 mg, 0.1643 mmol) in DMF(5 mL) at RT for 0.5 h to get the crude product. The resultant crude waspurified by 60-120 silica gel column chromatography using 2% methanol inDCM as eluent to obtain the title compound (350 mg, 89.74%). LCMS:m/z=480.2 (M+1)⁺.

Step 3: Preparation of5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 2 of example 38,4-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine(400 mg, 0.8333 mmol) was reduced with zinc dust (435 mg, 6.66 mmol) andammonium chloride (713 mg, 13.3 mmol) in THF/water (10/2 mL) to get thetitle compound (290 mg, 77.33%). LCMS: m/z=451.0 (M+1)⁺.

Step 4: Preparation of2-(2-acetamidopyridin-4-yl)-N-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(100 mg, 0.222 mmol), was coupled with2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylic acid (intermediate 20)(82 mg, 0.332 mmol) using HATU (108 mg, 0.288 mmol) and DIPEA (115 mg,0.888 mmol) in DMF (5 mL) to get the crude title compound (132 mg, 88%).LCMS: m/z=679.5 (M+1)⁺.

Step 5: Preparation of2-(2-acetamidopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 8 of example12-(2-acetamidopyridin-4-yl)-N-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide(132 mg, 0.1946 mmol) was deprotected using methanolic HCl/methanol (3mL) to get the title compound (20 mg, 18.34%).

1HNMR (DMSO-d₆, 400 MHz): δ 10.81 (s, 1H), 9.61 (s, 1H), 9.07 (s, 1H),8.93 (s, 1H), 8.79 (s, 1H), 8.56-8.55 (d, 1H), 7.66-7.65 (d, 1H), 4.81(s, 1H), 3.88 (s, 1H), 3.74 (s, 4H), 3.58 (s, 4H), 3.30-3.20 (m, 1H),3.14-3.11 (d, 1H), 2.72-2.60 (m, 3H), 2.15 (s, 3H), 2.05 (s, 1H), 1.86(s, 1H), 1.40-1.20 (m, 1H). LCMS: 49.65%, m/z=565.4 (M+1)⁺. HPLC:95.43%.

Example 1282-(2-aminopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamidehydrochloride

Step 1: Preparation of2-(2-aminopyridin-4-yl)-N-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 6 of example 1,5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(product of step 3 of example 128) (100 mg, 0.222 mmol), was coupledwith 2-(2-aminopyridin-4-yl)oxazole-4-carboxylic acid (intermediate 21)(68 mg, 0.333 mmol) using HATU (109 mg, 0.288 mmol) and DIPEA (114 mg,0.888 mmol) in DMF (5 mL) to get the title compound (120 mg, 85.71%).LCMS: m/z=637.4 (M+1)⁺.

Step 2: Preparation of2-(2-aminopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamidehydrochloride

Using the same reaction conditions as described in step 8 of example 1,2-(2-aminopyridin-4-yl)-N-(5-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide(120 mg, 0.188 mmol) was deprotected using methanolic HCl/methanol (5/2mL) to get the title compound (20 mg, 37.73%).

¹HNMR (DMSO-d₆, 400 MHz): δ 9.58 (s, 1H), 9.16 (s, 1H), 8.87 (s, 1H),8.20-8.19 (d, 1H), 7.53 (s, 1H), 7.28-7.27 (d, 1H), 3.90-3.80 (m, 1H),3.74 (s, 2H), 3.58 (s, 2H), 3.27-3.25 (m, 2H), 3.14-3.09 (m, 1H),2.90-2.70 (m, 2H), 2.76-2.73 (m, 2H), 2.10-1.70 (m, 6H). LCMS: 93.20%,m/z=523.4 (M+1)⁺. HPLC: 97.01%.

Example 1295-(2-aminopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)furan-2-carboxamidehydrochloride

Using the same reaction conditions as described in example 45,5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(product of step 3 of example 85) (155 mg, 0.3452 mmol), was coupledwith 5-(2-acetamidopyridin-4-yl)furan-2-carboxylic acid (intermediate22) (106 mg, 0.4315 mmol) using HATU (197 mg, 0.5188 mmol) and DIPEA(179 mg, 1.3835 mmol) in DMF (5 mL) to get the crude compound followedby deprotection using HCl/MeOH (5/5 mL) to get the title compound (50mg, 55%).

¹HNMR (CD₃OD, 300 MHz): δ 8.58 (s, 1H), 7.93-7.91 (d, 1H), 7.55-7.52 (m,2H), 7.48 (s, 1H), 7.41-7.38 (dd, 1H), 3.88-3.78 (m, 12H), 2.04-1.81 (m,5H). LCMS: 99.14%, m/z=522.3 (M+1)⁺.

HPLC: 97.06%.

Example 1302-(2-aminopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamidehydrochloride

Using the same reaction conditions as described in example 45,5-(4-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(product of step 3 of example 85) (100 mg, 0.222 mmol), was coupled with2-(2-aminopyridin-4-yl)oxazole-4-carboxylic acid (intermediate 21) (50mg, 0.244 mmol) using HATU (126 mg, 0.333 mmol) and DIPEA (114 mg, 0.888mmol) in DMF (3 mL) to get the crude compound followed by deprotectionusing methanolic HCl/MeOH (2/1 mL) to get the crude compound. This wasthen purified by prep HPLC and treated with methanolic HCl to get thetitle compound (27 mg, 31%).

¹HNMR (CD₃OD, 300 MHz): δ 8.95 (s, 1H), 8.868-8.864 (d, 1H), 8.05-8.03(d, 1H), 7.687-7.684 (d, 1H), 7.53-7.50 (dd, 1H), 3.87-3.84 (t, 4H),3.73 (s, 4H), 3.54-3.33 (m, 2H), 3.12-3.07 (m, 3H), 2.12-2.09 (m, 2H),1.90-1.87 (m, 2H). LCMS: 99.56%, m/z=523.2 (M+1)⁺. HPLC: 97.24%.

Example 1312-(2-aminopyridin-4-yl)-N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamidehydrochloride

Using the same reaction conditions as described in example 45,5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine(product of step 2 of example 98) (70 mg, 0.2 mmol) was coupled with2-(2-acetamidopyridin-4-yl)oxazole-4-carboxylic acid (intermediate 20)(62 mg, 0.24 mmol) using HATU (100 mg, 0.27 mmol) and DIPEA (110 mg,0.83 mmol) in DMF (0.3 mL) to afford the crude product followed bydeprotection using HCl/MeOH (0.5/2 mL) to get the crude compound. Thiswas then purified by prep HPLC and treated with methanol/ether HCl(0.5/0.5 mL) to get the title compound (30 mg).

¹HNMR (CD₃OD, 300 MHz): δ 8.90 (s, 1H), 8.86 (s, 1H), 8.03-8.02 (d, 1H),7.64-7.63 (d, 1H), 7.50-7.06 (dd, 1H), 3.86-3.83 (m, 4H), 3.73-3.70 (t,4H), 3.37-3.31 (m, 2H), 3.24-3.23 (m, 5H), 2.30-2.20 (m, 4H). LCMS:58.28%, m/z=525.2 (M+1)⁺. HPLC: 98.31%.

Example 132N-(5-(2-fluoropyridin-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of4-(5-(2-fluoropyridin-4-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine

Using the same reaction conditions as described in step 7 of example 1,4-(5-chloro-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine (product ofstep 4 of example 20) (200 mg, 0.666 mmol) was coupled with(2-fluoropyridin-4-yl)boronic acid (223 mg, 1 mmol) using sodium iodide(200 mg, 1.3 mmol), potassium carbonate (276 mg, 2 mmol) and Pd(dppf)Cl₂(48 mg, 0.067 mmol) in 1,2-dimethoxyethane/water (1/0.2 mL) to get thetitle compound (100 mg).

Step 2: Preparation of5-(2-fluoropyridin-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine

Using the same reaction conditions as described in step 5 of example 1,4-(5-(2-fluoropyridin-4-yl)-6-nitrothiazolo[4,5-b]pyridin-2-yl)morpholine(90 mg, 0.25 mmol) was reduced with zinc dust (130 mg, 1.99 mmol) andammonium chloride (212 mg, 3.98 mmol) in THF/water (2/1 mL) to get thetitle product (70 mg). LCMS: m/z=332.3 (M+1)⁺.

Step 3: Preparation ofN-(5-(2-fluoropyridin-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the similar reaction conditions as described in step 6 of example1, crude5-(2-fluoropyridin-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-amine (70mg, 0.21 mmol), was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxylic acid (52 mg, 0.25 mmol)using HATU (104 mg, 0.27 mmol) and DIPEA (110 mg, 0.84 mmol) in DMF (0.3mL) to get the title compound (100 mg).

¹HNMR (DMSO-d₆, 300 MHz): δ 10.40 (s, 1H), 8.92 (s, 1H), 8.67-8.65 (d,1H), 8.44 (s, 1H), 8.28-8.26 (d, 1H), 7.81 (s, 1H), 7.73-7.71 (d, 1H),7.63-7.61 (d, 1H), 7.44 (s, 1H), 3.75 (s, 4H), 3.65 (s, 4H), 2.56 (s,3H). LCMS: 100%, m/z=518.4 (M+1)⁺. HPLC: 96.41%.

Example 133N-(5-(4-fluoropiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Step 1: Preparation of1-(6-bromo-5-chlorothiazolo[4,5-b]pyridin-2-yl)piperidin-3-ol

Using the same reaction conditions as described in step 1 of example6,6-bromo-5-chloro-2-(methylthio)thiazolo[4,5-b]pyridine (product ofstep 2 of example 125) (1 g, 3.370 mmol) was substituted using3-hydroxypiperidine (510 mg, 5.06 mmol) in THF (10 mL) at 100° C. for 5h to obtain the crude product (280 mg). The crude product was purifiedby using 60-120 silica-gel column chromatography and compound was elutedusing 5% methanol in DCM as eluent to afford the title compound (1.1 g,94%).

Step 2: Preparation of6-bromo-2-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-5-chlorothiazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 2 of example 41,1-(6-bromo-5-chlorothiazolo[4,5-b]pyridin-2-yl)piperidin-3-ol (1 g,2.865 mmol) was protected using TBDMS chloride (863 mg, 5.73 mmol),imidazole (292 mg, 4.297 mmol) and DMAP (350 mg, 2.865 mmol) in DMF (5mL) at RT for 1 h to get the title compound (1.3 g, 100%). LCMS:m/z=464.2 (M+2)⁺.

Step 3: Preparation of1-(6-bromo-2-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)thiazolo[4,5-b]pyridin-5-yl)piperidin-4-ol

Using the same reaction conditions as described in step 1 of example 38,6-bromo-2-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-5-chlorothiazolo[4,5-b]pyridine(500 mg, 1.082 mmol) was substituted with 4-hydroxypiperidine (162 mg,1.623 mmol) using potassium carbonate (298 mg, 2.164 mmol) and DMF (1mL) at 160° C. for 14 h to afford the crude product. The crude productwas purified by using 60-120 silica-gel column chromatography andcompound was eluted using 2% methanol in DCM as eluent to afford thetitle compound (200 mg, 35%). LCMS: m/z=527.2 (M+2)⁺.

Step 4: Preparation of6-bromo-2-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-5-(4-fluoropiperidin-1-yl)thiazolo[4,5-b]pyridine

Using the same reaction conditions as described in step 2 of example 59,1-(6-bromo-2-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)thiazolo[4,5-b]pyridin-5-yl)piperidin-4-ol(200 mg, 0.378 mmol) was fluorinated using DAST (0.2 mL) in DCM (5 mL)at −20° C. for 1 h. The resultant crude was purified by 60-120 silicagel column chromatography using 50% ethyl acetate in hexane as eluent toobtain the title compound (120 mg). LCMS: m/z=529.3 (M)⁺.

Step 5: Preparation ofN-(2-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-5-(4-fluoropiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the same reaction conditions as described in step 5 of example125,6-bromo-2-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-5-(4-fluoropiperidin-1-yl)thiazolo[4,5-b]pyridine(120 mg, 0.226 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxamide (60 mg, 0.294 mmol)(Intermediate 23) using potassium phosphate (143 mg, 0.678 mmol), copperiodide (4 mg, 0.022 mmol) andtrans-N1,N2-dimethylcyclohexane-1,2-diamine (10 mg, 0.067 mmol) in1,4-dioxane (5 mL) at 110° C. for 14 h and purified by 60-120 silica gelcolumn chromatography using 2% methanol in DCM as eluent to obtain thecrude compound (100 mg). LCMS: m/z=652.4 (M+1)⁺.

Step 6: Preparation ofN-(5-(4-fluoropiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide

Using the similar reaction conditions as described in step 8 of example1,N-(2-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-5-(4-fluoropiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide(100 mg, 0.153 mmol) was deprotected using methanolic HCl (5 mL) andmethanol (1 mL) at RT for 0.5 h to afford the crude product. Theresultant crude was purified by prep HPLC to obtain the title compound(24 mg, 29.2%).

¹HNMR (CDCl₃, 400 MHz): δ 9.83 (s, 1H), 9.02 (s, 1H), 8.71-8.69 (d, 1H),8.41 (s, 1H), 7.83 (s, 1H), 7.72-7.70 (d, 1H), 5.00-4.75 (m, 1H),3.97-3.94 (m, 2H), 3.85-3.75 (m, 1H), 3.54-3.50 (m, 2H), 3.40-3.30 (m,2H), 3.13-3.11 (m, 2H), 2.68 (s, 3H), 2.24-2.20 (m, 4H), 2.00-1.99 (m,3H), 1.69-1.64 (m, 2H). LCMS: 93.92%, m/z=538.4 (M+1)⁺. HPLC: 95.18%.

Example 134N-(5-(4-aminopiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride

Step 1: Preparation of tert-butyl(1-(6-bromo-2-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)thiazolo[4,5-b]pyridin-5-yl)piperidin-4-yl)carbamate

Using the same reaction conditions as described in step 1 of example 38,6-bromo-2-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)-5-chlorothiazolo[4,5-b]pyridine(product of step 2 of example 134) (500 mg, 1.082 mmol) was substitutedwith tert-butyl piperidin-4-ylcarbamate (324 mg, 1.623 mmol) usingpotassium carbonate (298 mg, 2.164 mmol) and DMF (1 mL) at 150° C. for14 h to afford the crude product. The crude product was purified byusing 60-120 silica-gel column chromatography and compound was elutedusing 50% ethyl acetate in hexane as eluent to afford the title compound(100 mg, 14.7%). LCMS: m/z=628.4 (M+2)⁺.

Step 2: Preparation of tert-butyl(1-(2-(3-hydroxypiperidin-1-yl)-6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)thiazolo[4,5-b]pyridin-5-yl)piperidin-4-yl)carbamate

Using the same reaction conditions as described in step 5 of example125, tert-butyl(1-(6-bromo-2-(3-((tert-butyldimethylsilyl)oxy)piperidin-1-yl)thiazolo[4,5-b]pyridin-5-yl)piperidin-4-yl)carbamate(100 mg, 0.159 mmol) was coupled with2-(2-methylpyridin-4-yl)oxazole-4-carboxamide (42 mg, 0.207 mmol)(Intermediate 23) using potassium phosphate (101 mg, 0.477 mmol), copperiodide (3 mg, 0.015 mmol) andtrans-N1,N2-dimethylcyclohexane-1,2-diamine (7 mg, 0.047 mmol) in1,4-dioxane (5 mL) at 110° C. for 14 h and purified by 60-120 silica gelcolumn chromatography using 2% methanol in DCM as eluent to obtain thecrude compound (100 mg).

Step 3: Preparation ofN-(5-(4-aminopiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride

Using the similar reaction conditions as described in step 8 of example1, tert-butyl(1-(2-(3-hydroxypiperidin-1-yl)-6-(2-(2-methylpyridin-4-yl)oxazole-4-carboxamido)thiazolo[4,5-b]pyridin-5-yl)piperidin-4-yl)carbamate(100 mg, 0.153 mmol) was deprotected using methanolic HCl (5 mL) andmethanol (1 mL) at RT for 0.5 h to afford the crude product. Theresultant crude was purified by prep HPLC to obtain the title compound(20 mg, 28.1%).

¹HNMR (CD₃OD, 300 MHz): δ 8.96-8.92 (m, 2H), 8.76 (s, 1H), 8.60-8.58 (m,2H), 3.98-3.88 (m, 2H), 3.76-3.66 (m, 5H), 3.50-3.40 (m, 1H), 3.17-3.09(t, 2H), 2.94 (s, 3H), 2.13-1.96 (m, 7H), 2.35-2.20 (m, 2H). LCMS:98.18%, m/z=535.4 (M+1)⁺. HPLC: 96.08%.

Example 135N-(5-(2-hydroxypyridin-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamidehydrochloride

The solution ofN-(5-(2-fluoropyridin-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide(example 133) (100 mg, 0.19 mmol) in methanolic HCl (10 mL) was stirredat RT for 1 h and distilled out the solvent. The resultant crude waspurified by prep HPLC and treated with methanolic HCl to obtain thetitle compound (50 mg).

¹HNMR (CD₃OD, 300 MHz): δ 8.91-8.88 (m, 2H), 8.78 (s, 1H), 8.56 (s, 1H),8.48-8.46 (d, 1H), 7.83-7.80 (d, 1H), 7.12 (s, 1H), 7.97-7.95 (d, 1H),3.88 (s, 8H), 2.91 (s, 3H). LCMS: 100%, m/z=516.2 (M+1)⁺. HPLC: 98.02%.

IRAK-4 Biochemical Assay

Compounds were tested for their potential to inhibit IRAK-4 enzyme in aTR-FRET assay using recombinant IRAK-4 kinase from Millipore, USA. Theassay buffer was 50 mM Tris-HCl pH 7.5, 20 mM MgCl₂, 1 mM EGTA, 2 mMDTT, 3 mM MnCl₂ and 0.01% Tween20. 5 ng of IRAK-4 kinase was used forthe assay. After pre-incubation of enzyme with test compound for 30minutes at room temperature, a substrate mix containing 100 nM BiotinHistone H3 (Millipore, USA) and 20 μM ATP (Sigma, USA) was added and thereaction was incubated for 30 minutes. Post incubation, the reaction wasstopped by the addition of stop mix containing 40 mM EDTA, 1 nM ofEuropium-Anti-Phospho-Histone H3 (Ser10) antibody (Perkin Elmer, USA)and 20 nM Sure Light Allophycocyanin-Streptavidin (Perkin Elmer, USA).The fluorescence emission at 615 nm and 665 nm were measured at anexcitation of 340 nm and the percent inhibition was estimated from theratio of the fluorescence intensities[(F665/F615)*10000]. The compoundswere initially screened at 1 μM and 10 μM concentrations and potentcompounds (>50% inhibition at 1 μM) were taken for dose responsestudies. The IC₅₀ values were estimated by fitting the dose-responsedata to sigmoidal dose response (variable slope), curve fitting programusing Graphpad Prism software Version 6.01.

The compounds of the present invention were screened in the abovementioned assay and the results (IC₅₀) are summarized in the table 1.The IC₅₀ values of the compounds of examples are set forth below wherein“A” refers to an IC₅₀ value of less than or equal to 50 nM, “B” refersto IC₅₀ value ranges from 50.01 nM to 100 nM and “C” refers to an IC50value of greater than 100 nM.

TABLE 1 IC₅₀ values for IRAK4 activity of the selected compounds. GroupExample No A 3, 5, 7-8, 10-14, 16, 20-27, 29, 32-41, 43-45, 47, 50-67,69-78, 80, 82-102, 104, 110-111, 113-131 and 133-134. B 4, 6, 9, 42, 68and 79 C 17, 28, 30-31, 46, 48, 81, 103, 105-109 and 112

1-23. (canceled)
 24. A method of making a compound of formula (I) or apharmaceutically acceptable salt thereof, according to the followingscheme:

wherein: M is

L is NH₂ or halo; X₁ and X₃ independently are CH or N; X₂ is CR₂ or N,provided one and not more than one of X₁, X₂ or X₃ is N; A is O or S; Yis —CH₂— or O; Z is aryl or heterocyclyl; R₁, at each occurrence, isindependently halo or optionally substituted heterocyclyl, wherein thesubstituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl, hydroxyalkylor —NR_(a)R_(b); R₂ is hydrogen, optionally substituted cycloalkyl,optionally substituted aryl, optionally substituted heterocyclyl or—NR_(a)R_(b), wherein the substituent is alkyl, amino, halo or hydroxyl;R₃, at each occurrence, is alkyl or hydroxyl; R₁₀ is alkyl; R_(a) andR_(b) are independently hydrogen, alkyl, acyl, or heterocyclyl; m and nare independently 0, 1 or 2; p is 0 or 1; Q₁ is an amide couplingreagent, phosphorus-containing ligand, nitrogen-containing ligand, or isabsent; Q₂ is an activating agent, a transition metal catalyst, or isabsent; B is a base; and Sv is a solvent.
 25. The method of claim 24,wherein A is O or S; Y is —CH₂— or O; Z is aryl or heterocyclyl; R₁, ateach occurrence, is independently halo or optionally substitutedheterocyclyl, wherein the substituent is alkyl, aminoalkyl, halo, orNR_(a)R_(b); where R_(a) and R_(b) are independently hydrogen, alkyl, orheterocyclyl; R₂ is hydrogen, cycloalkyl, heterocyclyl or NR_(a)R_(b); mis 0; and n is
 1. 26. The method of claim 24, wherein A is O or S; Y is—CH₂— or O; Z is aryl or heterocyclyl; R₁, at each occurrence, isindependently halo or optionally substituted heterocyclyl; wherein thesubstituent is alkyl, alkoxy, aminoalkyl, halo, hydroxyl or NR_(a)R_(b);where R_(a) and R_(b) are independently hydrogen, alkyl, orheterocyclyl; R₂ is hydrogen, cycloalkyl, optionally substitutedheterocyclyl or NR_(a)R_(b), where the substituent is selected fromamino, halo or hydroxyl; ‘m’ and ‘n’ are independently 0, 1 or 2; and‘p’ is 0 or
 1. 27. The method of claim 24, wherein the group

wherein R₂ is as defined in claim
 24. 28. The method of claim 24,wherein the compound of formula (I) is a compound of formula (IA):

or a pharmaceutically acceptable salt thereof.
 29. The method of claim28, wherein A is O or S; Y is —CH₂— or O; R₁, at each occurrence, isindependently halo or optionally substituted heterocyclyl, wherein thesubstituent is alkyl, aminoalkyl, halo, or NR_(a)R_(b); where R_(a) andR_(b) are independently hydrogen, alkyl, or heterocyclyl; R₂ ishydrogen, cycloalkyl, heterocyclyl or NR_(a)R_(b); m is 0; and n is 1.30. The method of claim 28, wherein A is O or S; Y is —CH₂— or O; R₁, ateach occurrence, is independently halo or optionally substitutedheterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl,halo, hydroxyl or NR_(a)R_(b); where R_(a) and R_(b) are independentlyhydrogen, alkyl, or heterocyclyl; R₂ is hydrogen, cycloalkyl, optionallysubstituted heterocyclyl or NR_(a)R_(b), where the substituent isselected from amino, halo or hydroxyl; and ‘m’ and ‘n’ are independently0, 1 or
 2. 31. The method of claim 24, wherein the compound of formula(I) a compound of formula (IB):

or a pharmaceutically acceptable salt thereof.
 32. The method of claim31, wherein A is O or S; Y is —CH₂— or O; R₁, at each occurrence, isindependently halo or optionally substituted heterocyclyl, wherein thesubstituent is alkyl, aminoalkyl, halo, or NR_(a)R_(b); where R_(a) andR_(b) are independently hydrogen, alkyl, or heterocyclyl; R₂ ishydrogen, cycloalkyl, heterocyclyl or NR_(a)R_(b); and n is
 1. 33. Themethod of claim 31, wherein A is O or S; Y is —CH₂— or O; R₁, at eachoccurrence, is independently halo or optionally substitutedheterocyclyl; wherein the substituent is alkyl, alkoxy, aminoalkyl,halo, hydroxyl or NR_(a)R_(b); where R_(a) and R_(b) are independentlyhydrogen, alkyl, or heterocyclyl; and R₂ is hydrogen, cycloalkyl,optionally substituted heterocyclyl or NR_(a)R_(b), where thesubstituent is selected from amino, halo or hydroxyl.
 34. The method ofclaim 24, wherein the compound of formula (I) is a compound of formula(IC):

or a pharmaceutically acceptable salt thereof.
 35. The method of claim24, wherein L is NH₂; M is

Q₁ is an amide coupling reagent; Q₂ is an activating agent or absent; Bis a base and the base is a nitrogenous base; and Sv is a solvent, andthe solvent is an aprotic solvent.
 36. The method of claim 35, whereinQ₁ is N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (EDCI) or a saltthereof, or1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (HATU); Q₂ is hydroxybenzotriazole (HOBT) oris absent; B is diisopropylethylamine (DIPEA) or trimethylamine (TEA);and Sv is dimethyl formamide (DMF).
 37. The method of claim 36, whereinQ₁ is EDCI or a salt thereof; and Q₂ is HOBT.
 38. The method of claim36, wherein Q₁ is HATU; and Q₂ is absent.
 39. The method of claim 24,wherein L is halo; M is

R₁₀ is alkyl; Q₁ is a phosphorus-containing ligand or anitrogen-containing ligand; Q₂ is an a transition metal catalyst, orabsent; B is a base and the base is a carbonate base or phosphate base;and Sv is a solvent, and the solvent is an aprotic solvent or a proticsolvent.
 40. The method of claim 39, wherein M is

R₁₀ is tertiary butyl; Q₁ is2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (xphos),4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (xantphos),trans-N,N′-dimethylcyclohexane-1,2-diamine or is absent; Q₂ istris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃),bis(triphenylphosphine)palladium(II) dichloride (Pd(PPh₃)₂(Cl)₂), copperiodide (CuI), or is absent; B is a base and the base is a cesiumcarbonate, sodium carbonate, or potassium phosphate; and Sv is toluene,dimethoxyethane (DME), dioxane, water, or a combination thereof.
 41. Themethod of claim 40, wherein Q₁ is xphos; Q₂ is absent; B is cesiumcarbonate; and Sv is toluene.
 42. The method of claim 40, wherein Q₁ isxantphos; Q₂ is Pd₂(dba)₃; B is cesium carbonate; and Sv is toluene,dioxane, or a combination thereof.
 43. The method of claim 40, whereinQ₁ is absent; Q₂ is (Pd(PPh₃)₂(Cl)₂); B is sodium carbonate; and Sv isDME, water, or a combination thereof.
 44. The method of claim 40,wherein Q₁ is trans-N,N′-dimethylcyclohexane-1,2-diamine; Q₂ is CuI; Bis potassium phosphate; and Sv is dioxane.
 45. The method of claim 24,wherein the method further comprises a purification step.
 46. The methodof claim 45, wherein the purification step comprises columnchromatography, preparative thin layer chromatography, or highperformance liquid chromatography.
 47. The method of claim 24, whereinthe method further comprises a deprotection step comprising contactingthe reaction mixture with a deprotection agent, and the deprotectionagent is an acid or a source of fluoride.
 48. The method of claim 47,wherein the deprotection agent is methanolic hydrochloric acid ortetrabutylammonium fluoride (TBAF).
 49. The method of claim 24, whereinthe compound of formula (I) is selected from: Example No IUPAC name 1.6′-amino-N-(2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamide; 2.6′-amino-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamide hydrochloride; 3.N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride; 4.N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide hydrochloride; 5.N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 6.N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide; 7.2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 8.6-chloro-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide; 9.N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide; 10.2-(2-chloropyridin-4-yl)-N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 11.(S)-2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-3-ylamino)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 12.6′-amino-N-(2-morpholinooxazolo[5,4-b]pyridin-5-yl)-[2,3′-bipyridine]-6-carboxamide; 13.6′-amino-N-(2-morpholinothiazolo[4,5-c]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamide; 14.6′-amino-N-(2-morpholinothiazolo[5,4-b]pyridin-5-yl)-[2,3′-bipyridine]-6-carboxamide; 15.2-(2-methylpyridin-4-yl)-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 16.6′-amino-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)-[2,3′-bipyridine]-6-carboxamide; 17.N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide;18.3-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)benzamide; 19.2-(4-(aminomethyl)piperidin-1-yl)-5-fluoro-N-(2-morpholinothiazolo[4,5-b]pyridin-6-yl)benzamide; 20.2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 21.N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide; 22.N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1H-pyrazol-4-yl)picolinamide; 23.N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 24.N-(2,5-dimorpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 25.N-(5-(4-methylpiperazin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 26.N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide; 27.N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazole-4-carboxamide; 28.N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-hydroxypyridin-3-yl)oxazole-4-carboxamide; 29.2-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 30.N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-hydroxypyridin-3-yl)oxazole-4-carboxamide; 31.2-(2-methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 32.2-(2-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 33.2-(3-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 34.N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(3-methylpyridin-4-yl)oxazole-4-carboxamide; 35.2-(6-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 36.6-(1-methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide; 37.N-(2,5-di(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(6-methylpyridin-3-yl)oxazole-4-carboxamide; 38.(S)-N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 39.(S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 40.(R)-N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 41.(R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 42.(S)-2-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 43.(S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide; 44.(S)-6-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)picolinamide; 45.(S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 46.(S)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxamide; 47.(S)-2-(3-aminopyrrolidin-1-yl)-N-(5-cyclopropyl-2-morpholinooxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 48.2-(2-methylpyridin-4-yl)-N-(5-(piperidin-1-yl)-2-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride; 49.N-(2-(2,6-dimethylmorpholino)-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride; 50.N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(1-methyl-1H-pyrazol-4-yl)picolinamide hydrochloride; 51.6-(1-methyl-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide; 52.N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-3-yl)oxazole-4-carboxamide hydrochloride; 53.N-(2-((2S,6R)-2,6-dimethylmorpholino)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 54.2-(2-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 55.2-(2-hydroxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 56.N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methoxypyridin-4-yl)oxazole-4-carboxamide; 57.2-(6-methoxypyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 58.2-(2-methoxypyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 59.(S)-N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 60.2-(6-methylpyridin-3-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 61.2-(3-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 62.(S)-6-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide; 63.(S)-6-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide; 64.(S)-6-(3-aminopyrrolidin-1-yl)-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide; 65.(S)-N-(2,5-di(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide; 66.(S)-2-(3-aminopyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 67.(S)-N-(5-(3-aminopyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 68.(S)-2-(3-aminopyrrolidin-1-yl)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 69.N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 70.(S)-2-(3-hydroxypyrrolidin-1-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 71.(S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 72.(S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide; 73.(S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(3-hydroxypyrrolidin-1-yl)oxazole-4-carboxamide; 74.(S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)picolinamide; 75.(S)-N-(5-cyclopropyl-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)oxazole-4-carboxamide; 76.N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide; 77.(S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide; 78.(R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide; 79.(S)-N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-6-(3-hydroxypyrrolidin-1-yl)picolinamide; 80.N-(5-(3-hydroxyazetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 81.(S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide; 82.(S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; 83.(S)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 84.N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide 85.(R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 86.N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; 87.N-(5-(azetidin-1-yl)-2-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 88.2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 89.2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 90.5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)furan-2-carboxamide; 91.N-(5-(azepan-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 92.2-(2-aminopyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride; 93.N-(5-(azetidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 94.(R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 95.(R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; 96.(S)-6-(1-(2-hydroxypropyl)-1H-pyrazol-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)picolinamide 97.N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide 98.N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride 99.N-(5-(1-methyl-1H-pyrazol-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 100.N-(5-(3-fluorophenyl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 101.N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; 102.N-(5-(3-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; 103.(S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide; 104.N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 105.(R)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide; 106.N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(6-methoxypyridin-3-yl)oxazole-4-carboxamide; 107.(S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; 108.(S)-N-(5-(3-hydroxypyrrolidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)thiophene-2-carboxamide; 109.N-(5-(azetidin-1-yl)-2-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 110.2-(2-methylpyridin-4-yl)-N-(2-(piperidin-1-yl)-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 111.5-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(piperidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)furan-2-carboxamide; 112.N-(5-(azetidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 113.2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(pyrrolidin-1-yl)oxazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 114.N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; 115.(R)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-5-(2-methylpyridin-4-yl)furan-2-carboxamide; 116.N-(5-(furan-3-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 117.N-(5-(3-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 118.N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 119.N-(5-(4-fluoropiperidin-1-yl)-2-morpholinooxazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 120.(S)-N-(5-(3-aminopiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 121.2-(2-methylpyridin-4-yl)-N-(2-morpholino-5-(1H-pyrazol-4-yl)thiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 122.N-(5-(6-fluoropyridin-3-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 123.N-(5-(3-hydroxy-8-azabicyclo[3.2.1]octan-8-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 124.N-(2-(3-hydroxypiperidin-1-yl)-5-(piperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 125.2-(2-acetamidopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 126.N-(2-(3-hydroxypiperidin-1-yl)-5-(4-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 127.2-(2-acetamidopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide; 128.2-(2-aminopyridin-4-yl)-N-(5-(3-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride; 129.5-(2-aminopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)furan-3-carboxamide hydrochloride; 130.2-(2-aminopyridin-4-yl)-N-(5-(4-hydroxypiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride; 131.2-(2-aminopyridin-4-yl)-N-(5-(4-fluoropiperidin-1-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)oxazole-4-carboxamide hydrochloride; 132.N-(5-(2-fluoropyridin-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 133.N-(5-(4-fluoropiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide; 134.N-(5-(4-aminopiperidin-1-yl)-2-(3-hydroxypiperidin-1-yl)thiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride; and135.N-(5-(2-hydroxypyridin-4-yl)-2-morpholinothiazolo[4,5-b]pyridin-6-yl)-2-(2-methylpyridin-4-yl)oxazole-4-carboxamide hydrochloride;

or a pharmaceutically acceptable salt thereof.